Intrinsic and adaptive resistance hampers the success of antiangiogenic therapies (AAT), especially in breast cancer where this treatment modality has proven largely ineffective. Therefore, novel ...strategies to improve the efficacy of AAT are warranted. Solid tumors such as breast cancer are characterized by a high infiltration of myeloid-derived suppressor cells (MDSC), which are key drivers of resistance to AAT. Therefore, we hypothesized that all-
retinoic acid (ATRA), which induces differentiation of MDSC into mature cells, could improve the therapeutic effect of AAT. ATRA increased the efficacy of anti-VEGFR2 antibodies alone and in combination with chemotherapy in preclinical breast cancer models. ATRA reverted the anti-VEGFR2-induced accumulation of intratumoral MDSC, alleviated hypoxia, and counteracted the disorganization of tumor microvessels. Mechanistic studies indicate that ATRA treatment blocked the AAT-induced expansion of MDSC secreting high levels of vessel-destabilizing S100A8. Thus, concomitant treatment with ATRA holds the potential to improve AAT in breast cancer and possibly other tumor types.
Increasing the therapeutic efficiency of antiangiogenic drugs by reducing resistance-conferring myeloid-derived suppressor cells might improve breast cancer treatment.
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The fine equilibrium of bone homeostasis is maintained by bone-forming osteoblasts and bone-resorbing osteoclasts. Here, we show that TAM receptors MERTK and TYRO3 exert reciprocal effects in ...osteoblast biology: Osteoblast-targeted deletion of MERTK promotes increased bone mass in healthy mice and mice with cancer-induced bone loss, whereas knockout of TYRO3 in osteoblasts shows the opposite phenotype. Functionally, the interaction of MERTK with its ligand PROS1 negatively regulates osteoblast differentiation via inducing the VAV2-RHOA-ROCK axis leading to increased cell contractility and motility while TYRO3 antagonizes this effect. Consequently, pharmacologic MERTK blockade by the small molecule inhibitor R992 increases osteoblast numbers and bone formation in mice. Furthermore, R992 counteracts cancer-induced bone loss, reduces bone metastasis and prolongs survival in preclinical models of multiple myeloma, breast- and lung cancer. In summary, MERTK and TYRO3 represent potent regulators of bone homeostasis with cell-type specific functions and MERTK blockade represents an osteoanabolic therapy with implications in cancer and beyond.
Although inhibitors of bromodomain and extra terminal domain (BET) proteins show promising clinical activity in different hematologic malignancies, a systematic analysis of the consequences of ...pharmacological BET inhibition on healthy hematopoietic (stem) cells is urgently needed. We found that JQ1 treatment decreases the numbers of pre-, immature and mature B cells while numbers of early pro-B cells remain constant. In addition, JQ1 treatment increases apoptosis in T cells, all together leading to reduced cellularity in thymus, bone marrow and spleen. Furthermore, JQ1 induces proliferation of long-term hematopoietic stem cells, thereby increasing stem cell numbers. Due to increased numbers, JQ1-treated hematopoietic stem cells engrafted better after stem cell transplantation and repopulated the hematopoietic system significantly faster after sublethal myeloablation. As quantity and functionality of hematopoietic stem cells determine the duration of life-threatening myelosuppression, BET inhibition might benefit patients in myelosuppressive conditions.
BCR‐ABL negative myeloproliferative neoplasms (MPNs) consist of essential thrombocythemia, polycythemia vera, and myelofibrosis. The majority of patients harbor the JAK2‐activating mutation V617F. ...JAK2 inhibitors were shown to reduce symptom burden and splenomegaly in MPN patients. However, treatment options are limited after failure of JAK2 inhibitors. AXL, a member of the TAM family of receptor tyrosine kinases, mediates survival and therapy resistance of different myeloid cancers including acute myeloid leukemia and chronic myeloid leukemia. We studied the relevance of AXL as a target in MPN using primary patient cells and preclinical disease models. We found that AXL is abundantly activated in MPN cells and that its ligand growth arrest‐specific gene 6 is upregulated in MPN patients. Pharmacologic and genetic blockade of AXL impaired viability, decreased proliferation and increased apoptosis of MPN cells. Interestingly, ruxolitinib treatment induced increased phosphorylation of AXL indicating that activation of AXL might mediate resistance to ruxolitinib. Consistently, the AXL inhibitor bemcentinib exerted additive effects with ruxolitinib via impaired STAT3, STAT5, and AKT signaling. Both agents had activity when employed alone and exerted an additive effect on survival and splenomegaly in vivo. Moreover, bemcentinib treatment normalized red blood cell count and hemoglobin levels in vivo. Thus, our data indicate that AXL inhibition represents a novel treatment option in MPN warranting clinical investigation.
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Acute myeloid leukemia can be treated by intensive chemotherapy. However, this treatment is unsuitable for a subset of patients because of age and/or co-morbidities. Such patients benefit from ...hypomethylating agents and venetoclax but frequently develop resistance to this treatment regimen. This calls for the development of novel drugs that can prolong survival in AML patients unfit for intensive chemotherapy. The receptor tyrosine kinase AXL is a negative prognostic factor in AML. Its activation promotes survival, chemoresistance and proliferation of AML blasts. In addition, it is also present on innate immune cells and contributes to the formation of immunosuppressive environments. Together, this makes AXL a promising target for the treatment of AML. Bemcentinib is a first-in-class, orally available, selective inhibitor of AXL. Here, we report a single-cell translational sub-study in a sub-cohort of patients unfit for intensive chemotherapy (B2+B5) from the phase Ib/II clinical trial BGBC003 (NCT02488408). This sub-cohort was treated by a combination of bemcentinib and low-dose cytarabine (LDAC). To gain first insights into the mechanisms underlying treatment response, we conducted a translational study evaluating 13 participating patients. Among 32 patients evaluated for efficacy, 8 patients responded to their treatment (objective response rate: 25%). Among patients who received previous therapy ( i.e. relapsed/refractory patients), objective response rate was 18.5% (5/27). The median overall survival was 8.0 months, with a notable survival benefit (median overall survival of 24.8 months) in responders. Relapsed/refractory patients exhibited a median overall survival of 7.8 months. These data highlight that bemcentinib-LDAC benefits a considerable subset of AML patients unfit for intensive chemotherapy. In order to gain mechanistic insights into the efficacy of bemcentinib-LDAC, we profiled cells from bone marrows of 13 participating patients (6 responders, 7 non-responders, according to best response) using single-cell transcriptomics and multi-omics (CITE-seq). Cell type annotation highlighted various immune cell populations next to AML blasts. Successful treatment was associated with stronger TNFα signaling in blasts before treatment. A tight link between TNFα and AXL could subsequently be established in vitro as several AML cell lines up-regulated expression of AXL upon exposure to TNFα. Inhibiting AXL in these cell lines using bemcentinib increased expression of TNFα. This indicates a potential negative feedback loop between these two players. Furthermore, cytotoxic immune cells (CD8 + effector T cells, γδ T cells and natural killer cells) from responders displayed evidence for increased pro-inflammatory signaling upon bemcentinib-LDAC treatment. This included TNFα signaling programs next to IFNα and IFNγ signaling programs. Thus, our data indicate that bemcentinib-LDAC promotes the activity of such cytotoxic cells. In line with this, we observed increasing crosstalk between immune cells upon bemcentinib-LDAC treatment in responders. Importantly, cells from non-responders generally exhibited the opposite trend, highlighting the aforementioned cell types and pathways as factors that distinguish responders from non-responders. Together, our results indicate a potential role of TNFα and cytotoxic immune cells in the successful application of bemcentinib-LDAC. In conclusion, our findings warrant further clinical development of bemcentinib-LDAC for AML patients unfit for intensive chemotherapy. Additionally, extended research on TNFα and cytotoxic immune cells may lead to a better understanding of what mechanisms cause a treatment response. This may ultimately enable an accurate selection of patients who will benefit from bemcentinib-LDAC.
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Axl, a member of the TAM family of receptor tyrosine kinases, mediates survival and therapy resistance of different cancer cells. The Axl ligand growth-arrest specific gene 6 (Gas6) was discovered to ...promote proliferation of leukemia cells in acute and chronic myeloid leukemia and Axl was identified as a potential therapeutic target in these diseases. Based on these data we investigated the role of Axl in BCR-ABL negative myeloproliferative neoplasms (MPN) and the therapeutic potential of Axl blockade in this group of diseases.
We studied the effects of Axl blockade using the small molecule Axl inhibitor BGB324 and performing a lentivirus shRNA mediated knockdown of Axl in human SET-2 and murine BaF3-Jak2V617F MPN cell lines. Pharmacologic Axl blockade resulted in a significant dose dependent decrease in viability of MPN cell lines as measured by WST-1 cell viability assay. Annexin+ staining revealed an increased rate of apoptotic cells upon BGB324 treatment for SET-2 (increase by 15% at 1µM, p<0.001) and BaF3-Jak2V617F cells (increase by 54% at 2µM, p<0.05). Moreover, Western Blot analysis showed higher levels of cleaved caspase 3 in BGB324 treated SET-2 cells and decreased levels of anti-apoptotic bcl-2 in BGB324 treated BaF3-Jak2V617F cells. Additionally, BrdU incorporation assays showed a dose dependent decrease in proliferating cells upon treatment with BGB324 in MPN cell lines (p<0.05). Genetic knockdown of Axl in SET-2 cells decreased cell viability by 75% (p<0.01), increased apoptosis levels as measured by Annexin+ staining by 61% (p<0.05) and decreased proliferation as measured by BrdU incorporation by 35% (p<0.001) compared to control-transduced cells. Furthermore, Western Blot analysis revealed that genetic knockdown of Axl resulted in decreased phosphorylation of Stat3 and Stat5 compared to control-transduced cells. Combined Axl and Jak2 blockade, using BGB324 and the Jak2-inhibitor ruxolitinib, showed additive effects on reducing cell viability in SET-2 and BaF3-Jak2V617F cells (p<0.01 and p<0.001, respectively). Western Blot analysis identified inhibition of Stat5 by BGB324 single treatment in SET-2 cells whereas additive effects of combined Axl and Jak2 blockade resulted from additional inhibition of Stat3. In BaF3-Jak2V617F cells, BGB324 single treatment resulted in downstream inhibition of Akt signaling whereas additive effects of combined Axl and Jak2 blockade were exerted via additional inhibition of Stat5, Stat3 and Erk.
The finding that BGB324 inhibits growth of MPN cells was further corroborated in vivo. A xenograft tumor model with SET-2 cells was set up in vivo. SET-2 tumor bearing mice treated with BGB324 50mg/kg showed a slower tumor growth (n=8, p<0.01), with a 60% reduction of tumor weight compared to vehicle treated mice (n=8/8, p<0.01). As a second in vivo model, a systemic model of Jak2V617F driven disease was used. After intravenous injection of BaF3-Jak2V617F cells, mice were treated with 50mg/kg BGB324 or vehicle starting the day after inoculation. BGB324 treated mice had a longer overall survival compared to vehicle treated mice (n=10/11, p*<0.05).
Furthermore, to evaluate the potential of BGB324 in primary MPN cells, peripheral blood mononuclear cells (PBMC) were isolated from MPN patients and healthy donors. Western Blot analysis showed higher levels of Axl expression by PBMC from MPN patients compared to PBMC from healthy donors. Moreover, colony-forming assays with PBMC were performed in the presence of different concentrations of BGB324. Here, a higher reduction in the number of colony forming units (BFU-E and CFU-GEMM) was observed in samples from MPN patients compared to healthy donors upon treatment with 1µM (77% vs. 5%, respectively; p<0.001) or 2µM (100% vs. 60%, respectively; p<0.01) of BGB324 (n=5/5).
In conclusion, these data indicate therapeutic potential of Axl blockade in BCR-ABL negative MPN as monotherapy and in combination with Jak2-inhibition, supporting the need for clinical investigation.
von Amsberg:Novartis: Honoraria, Speakers Bureau; Ipson: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau; Astellas: Honoraria, Speakers Bureau; MSD: Honoraria, Speakers Bureau. Loges:BerGenBio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Despite many therapeutic advances in recent years Multiple Myeloma (MM) still remains incurable in the majority of the patients. In addition, MM patients suffer significantly from co-morbidities ...including bone pain and renal insufficiency. Therefore, the development of novel treatments is warranted. The TAMR family consists of Tyro3, Axl and Mer which represent evolving targets in cancer. We demonstrated that the role of TAMR is non-redundant in hematologic malignancies, with Axl exerting an important function in AML, but not in MM, where Mer represents a novel target.
Therefore, we tested the therapeutic potential of the Mer-inhibitor R992, which has an 8-fold selectivity over Tyro3 and a 13-fold selectivity over Axl in preclinical MM models (Rigel, San Francisco, USA).
R992 exerted a dose-dependent growth inhibition of U266, JJN3 and RPMI8226 cells in vitro (n=3, *p<0.001). Mechanistically, Mer blockade inhibited proliferation in 5-bromo-2′-deoxyuridine assays and induced apoptosis as shown by increased numbers of Annexin V+ cells (n=3,*p<0.05 and *p<0.001, respectively). To delineate signaling pathways mediating the biological effects of Mer blockade in MM cells we investigated key mediators of MM cell proliferation and survival. Here, we found reduced phosphorylation of Akt upon Mer inhibition with R992. Furthermore, R992 inhibited mitogen-activated protein kinase (MAPK) pathways Erk and p38. Subsequently, we investigated whether inhibition of Mer signaling increases chemosensitivity of MM cells. Combination treatment of R992 with bortezomib and cyclophosphamide demonstrated that Mer inhibition significantly increased sensitivity of MM cells to these established MM therapies.
Oral administration of 60mg/kg R992 BID to mice significantly reduced tumor burden in the U266 systemic myeloma mouse model. The λ light chain concentration and the CD138+ MM cell load was reduced 2-fold in R992 treated mice compared to placebo-treated mice 8 weeks after injection (n=5/5, *p<0.05 and n=4/5, *p<0.05, respectively). Importantly, treatment with R992 resulted in a significant prolongation of overall survival by 15 days in the U266 model (median OS 73 vs. 88 days (n=13/12, *p<0.05). In addition, treatment with R992 prolonged survival in the more aggressive JJN3 model (median OS 24 vs. 27 days, n=9/7, *p<0.005).
For further phenotyping of the effects of R992 we performed microcomputed tomography (µCT) and histological analysis of the tibias in the U266 model. µCT analysis of proximal tibia metaphyses revealed, that bone volume and bone mineral density (BMD) were significantly increased by R992 (n=7/7, *p<0.05). Moreover, analysis of the metaphyseal spongiosa showed that R992 could retard myeloma-mediated destruction of trabecular bone area measured by increased trabecular number and increased trabecular thickness (n=7/7, *p<0.05). Interestingly, R992 could also enlarge the metaphyseal diameter due to thickened cortical bone. Vice versa, overexpression of the Mer ligands Gas6 and Pros1 in U266 and JJN3 cells led to increased osteoclast and decreased osteoblast differentiation in vitro and more rapid and destructive myeloma bone disease in vivo. These data suggest that the expression of Mer ligands represent thus far unrecognized mediators of MM-induced perturbed bone homeostasis.
To directly assess the effect of R992 on osteoclasts, we treated osteoclast cultures with R992 and observed an inhibition of osteoclast differentiation by R992 alone and in co-culture with myeloma cells. Western blot analysis confirmed, that Mer phosphorylation was reduced by R992, whereas the phosphorylation of Tyro3 was not altered. Concomitantly, phosphorylation of p38 and activation of non-canonical NFκB pathway showed a dose dependent reduction after Mer blockade. Interestingly, R992 led also to increased osteoblast differentiation and could restore myeloma mediated osteoblast inhibition in co-cultures of MM cells and osteoblasts.
In summary, our data suggest that Mer blockade leads to inhibition of MM and its associated bone disease. Furthermore, the function of Mer in bone homeostasis promoting osteoclast and inhibiting osteoblast activity leads to the potential application of Mer inhibitors also in osteolytic bone metastases or osteoporosis.
Darwish:Rigel Pharmaceuticals: Employment. Bhamidipati:Rigel Pharmaceuticals: Employment. Masuda:Rigel Pharmaceuticals: Employment, Equity Ownership. Loges:BerGenBio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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We analyzed the predictive potential of pretreatment soluble carbonic anhydrase IX levels (sCAIX) for the efficacy of bevacizumab in the phase III neoadjuvant GeparQuinto trial. sCAIX was determined ...by enzyme‐linked immunosorbent assay (ELISA). Correlations between sCAIX and pathological complete response (pCR), disease‐free and overall survival (DFS, OS) were assessed with logistic and Cox proportional hazard regression models using bootstrapping for robust estimates and internal validation. 1,160 HER2‐negative patient sera were analyzed, of whom 577 received bevacizumab. Patients with low pretreatment sCAIX had decreased pCR rates (12.1 vs. 20.1%, p = 0.012) and poorer DFS (adjusted 5‐year DFS 71.4 vs. 80.5 months, p = 0.010) compared to patients with high sCAIX when treated with neoadjuvant chemotherapy (NCT). For patients with low sCAIX, pCR rates significantly improved upon addition of bevacizumab to NCT (12.1 vs. 20.4%; p = 0.017), which was not the case in patients with high sCAIX (20.1% for NCT vs. 17.0% for NCT‐B, p = 0.913). When analyzing DFS we found that bevacizumab improved 5‐year DFS for patients with low sCAIX numerically but not significantly (71.4 vs. 78.5 months; log rank 0.234). In contrast, addition of bevacizumab worsened 5‐year DFS for patients with high sCAIX (81 vs. 73.6 months, log‐rank 0.025). By assessing sCAIX levels we identified a patient cohort in breast cancer that is potentially undertreated with NCT alone. Bevacizumab improved pCR rates in this group, suggesting sCAIX is a predictive biomarker for bevacizumab with regards to treatment response. Our data also show that bevacizumab is not beneficial in patients with high sCAIX.
What's new?
While the addition of bevacizumab to neoadjuvant therapy can improve rates of pathological complete response (pCR) in different malignancies, a biomarker to identify patients likely to benefit from the combined therapy is lacking. In this study, serum soluble carbonic anhydrase IX (sCAIX) was identified as a marker for the selection of patients with early breast cancer responding to combined bevacizumab and neoadjuvant chemotherapy. Significant improvements in pCR rates were observed in patients with low sCAIX levels. The addition of bevacizumab further improved 5‐year disease‐free survival in low sCAIX patients, while having detrimental effects in patients with high sCAIX levels.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background/significance: Bromodomain and extra terminal domain (BET) proteins have been shown to be critical for maintaining the function of leukemia stem cells. Although BET-inhibitors are in ...clinical development and show promising activity in different hematologic malignancies, a systematic analysis of the consequences of pharmacological BET-inhibition on healthy hematopoietic (stem) cells is outstanding.
Methods: C57BL/6J (WT) or B6.SJL-Ptprca Pepcb/BoyJ mice, which carry the congenic pan-leukocyte marker CD45.1 were treated for 3 weeks with the BET-Inhibitor JQ1 or a placebo. For competitive repopulation transplantations, bone marrow from treated CD45.1 mice was transplanted together with WT competitor cells (CD45.2) into lethally irradiated WT mice (9 Gy) in different ratios. Engraftment of all major hematopoietic lineages was monitored in peripheral blood (PB) and BM using differential blood counting and flow cytometry. For the determination of HSC frequency in vivo, extreme limiting dilution analysis (ELDA) was carried out by transplanting 2x103, 2x104 or 2x105 JQ1- or placebo-treated bone marrow cells from WT mice together with 2x105 bone marrow cells from CD45.2 mice. Engraftment was assumed when CD45.1+ myeloid cells were present in the peripheral blood in frequencies > 1 %.
Colony formation assays were used to measure the abundance of colony forming progenitor cells (M3434) as well as megakaryocytic progenitors (MegaCult-C). For analysis of recovery after myelosuppression, JQ1- or placebo-treated WT mice received sublethal irradiation (5 Gy) and hematopoietic repopulation was monitored. For analysis of HSC proliferation, 1 mg BrdU was injected 24 h, 12 h, and 6 h before sacrifice.
Results: As a first step, we analyzed the mRNA expression patterns of Brd2-4 in all major hematopoietic subpopulations, because BET-family members represent the main molecular targets of JQ1. Expression of Brd4 mRNA is most abundant in megakaryocytes (MK), followed by B cells, T cells and hematopoietic stem cells (HSC) and expression levels of Brd2+3 show similar distribution.
JQ1-treatment decreases the numbers of pre-, immature and mature B cells while numbers of early pro-B cells remain constant (pre-B cells: 125 ± 7 vs. 52 ± 5 and immature B cells: 121 ± 9 vs. 26 ± 5 x104 cells/tibia; n=4; *p<0.05). Furthermore, it increases apoptosis in all T cell subsets, all together leading to reduced cellularity in thymus, BM and spleen. Intriguingly, JQ1 induces a 3-fold increase in the number of hematopoietic stem and progenitor cells (25 ± 2 vs. 70 ± 5 x103 LSK/femur; n=5; *p<0.05) and mobilizes HSC into the peripheral blood (4 ± 1 vs. 28 ± 2 x106 CFU/ml blood; n=5; *p<0.05). Consistently, extreme limiting dilution analysis (ELDA) showed a 3-fold increase in stem cell frequencies in the bone marrow upon JQ1-treatment (1/19480 vs. 1/6284; n=8-12; *p<0.05).
We found that the elevated HSC numbers arise from increased cycling of LT-HSC, as these cells incorporate more BrdU upon JQ1-treatment (29 ± 2 vs. 41 ± 3 % BrdU+ LT-HSC in bone marrow; n=5; *p<0.05). Moreover and in contrast to placebo, JQ1-treated bone marrow cells preserve their colony-forming properties during several rounds of replating in vitro, indicating sustained stemness (18 ± 4 vs. 77 ± 10 CFU/1x104 bone marrow cells after third replating; n=3-8; *p<0.05). Due to increased numbers of HSC, JQ1-treated bone marrow engrafts better after competitive stem cell transplantation and repopulates the hematopoietic system significantly faster after sublethal myeloablation. Six weeks after irradiation, total leukocyte counts of JQ1-treated mice fully recover to levels before irradiation (94 ± 7 % recovery; n=5; *p<0.05), whereas recovery is slower in the control group (47 ± 5 % recovery; n=5; *p<0.05).
Conclusions: JQ1 induces proliferation and mobilization of HSC, thereby increasing their number in bone marrow and peripheral blood. Therefore, BET-inhibition might benefit patients after myelosuppression or stem cell transplantation.
Loges:BerGenBio ASA: Research Funding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Immune therapies have revolutionized the treatment of cancer, however, until now only a minority of patients derive long-term benefit. Notably, despite widely reported significant ...differences between the immune system of males and females, there continues to exist a knowledge gap regarding sex disparities in anti-cancer immune responses. Recent meta-analyses indicate that immune checkpoint blockade (ICB) treatment has higher efficacy in male patients compared to females, regardless of the cancer type. To investigate the mechanisms underlying these sex-specific differences we utilized the syngeneic colorectal cancer model MC38 because it mirrors the clinical situation yielding responding and non-responding mice. Therefore, we inoculated tumor cells subcutaneously (s.c.) into male and female mice, and treated them with either IgG2a control Ab or anti-PD1 Ab. When analyzing the tumor response to anti-PD1 treatment we observed significant sex-biased growth kinetics upon ICB favoring males. To asses a potential role of androgens in impacting observed sex differences to ICB response in vivo, we performed surgical androgen deprivation therapy (orchiectomy) in male mice, as well as sham-surgery in male and female mice as control. After a recovery period, we proceeded with s.c. cell injection and ICB treatment as previously described. Sham male mice showed a very high response rate to anti-PD1 (92%) compared to sham females (58%), but more importantly, testosterone suppression by surgical androgen deprivation therapy led to a lower response rate of castrated mice (71%). To further confirm whether the presence of testosterone was beneficial for ICB response, we implanted s.c. sham or testosterone pumps into male and female mice and proceeded as before. Males with sham pumps showed a very high response rate to anti-PD1 (90%) compared to females with sham pumps (50%), while testosterone supplementation in females led to enhanced response rate (85%). Overall, this demonstrated that regardless of biological sex, presence of testosterone is sufficient to positively impact ICB therapy outcome. Furthermore, immunophenotyping analysis by flow cytometry showed that females supplemented with testosterone and treated with anti-PD1 had significantly increased intratumoral stem-like CD8+TCF1+PD1+ T cells compared to sham females. Additionally, these findings also correlated with enhanced intratumoral terminal differentiated effector CD8+TCF1-PD1+ T cells in both sham males and females supplemented with testosterone, compared to sham females. In summary, androgens can modulate anti-cancer immune responses by contributing to a more sustained anti-tumor CD8+ T cell response and consequently better responses upon treatment with anti-PD1. These findings are in concordance with male cancer patients responding better to ICB and warrant therapy escalation in female patients.
Citation Format: María Elena Vargas-Delgado, Lara Meier, Jonas Waizenegger, Julia Oberbauer, Nikolaus Berenbrok, Janik Engelmann, Victoria Gensch, Franziska Heilmann, Jochim Reinert, Kristoffer Riecken, Boris Fehse, Hannelore Lotter, Dorothee Schwinge, Christoph Schramm, Hans-Willi Mittruecker, Isabel Ben-Batalla, Sonja Loges. Presence of androgens improves efficacy of PD1 blockade abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5830.
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