The number of clinical protocols testing combined therapies including immune check-point inhibitors and platinum salts is currently increasing in lung cancer treatment, however preclinical studies ...and rationale are often lacking. Here, we evaluated the impact of cisplatin treatment on PD-L1 expression analyzing the clinicopathological characteristics of patients who received cisplatin-based neoadjuvant chemotherapy followed by surgery and showed that cisplatin-based induction treatment significantly increased PD-L1 staining in both tumor and immune cells from the microenvironment. Twenty-two patients exhibited positive PD-L1 staining variation after neoadjuvant chemotherapy; including 9 (23.1%) patients switching from <50% to ≥50% of stained tumor-cells. We also confirmed the up-regulation of PD-L1 by cisplatin, at both RNA and protein levels, in nude and immunocompetent mice bearing tumors grafted with A549, LNM-R, or LLC1 lung cancer cell lines. The combined administration of anti-PD-L1 antibodies (3 mg/kg) and cisplatin (1 mg/kg) to mice harboring lung carcinoma significantly reduced tumor growth compared to single agent treatments and controls. Overall, these results suggest that cisplatin treatment could synergize with PD-1/PD-L1 blockade to increase the clinical response, in particular through early and sustainable enhancement of PD-L1 expression.
•Cisplatin-based induction chemotherapy increases PD-L1 expression by tumor cells.•PD-L1 staining of microenvironment immune cells was higher after neoadjuvant treatment.•Cisplatin rapidly increases PD-L1 mRNA and protein levels in lung cancer cell lines.•In tumor bearing mice injection of cisplatin significantly enhances PD-L1 expression.•The combined treatment associating cisplatin and anti-PD-L1 improves tumor response.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
By unlocking antitumor immunity, antibodies targeting programmed cell death 1 (PD-1) exhibit impressive clinical results in non-small cell lung cancer, underlining the strong interactions between ...tumor and immune cells. However, factors that can robustly predict long-lasting responses are still needed.
We performed in-depth immune profiling of lung adenocarcinoma using an integrative analysis based on immunohistochemistry, flow-cytometry, and transcriptomic data. Tumor mutational status was investigated using next-generation sequencing. The response to PD-1 blockers was analyzed from a prospective cohort according to tumor mutational profiles and PD-L1 expression, and a public clinical database was used to validate the results obtained.
We showed that distinct combinations of
, and
mutations were major determinants of the tumor immune profile (TIP) and of the expression of PD-L1 by malignant cells. Indeed, the presence of
mutations without co-occurring
or
alterations (
-mut/
-
-WT), independently of
mutations, identified the group of tumors with the highest CD8 T-cell density and PD-L1 expression. In this tumor subtype, pathways related to T-cell chemotaxis, immune cell cytotoxicity, and antigen processing were upregulated. Finally, a prolonged progression-free survival (PFS: HR = 0.32; 95% CI, 0.16-0.63,
< 0.001) was observed in anti-PD-1-treated patients harboring
-mut/
-
-WT tumors. This clinical benefit was even more remarkable in patients with associated strong PD-L1 expression.
Our study reveals that different combinations of
, and
mutations, together with PD-L1 expression by tumor cells, represent robust parameters to identify best responders to PD-1 blockade.
.
Clear cell renal cell carcinoma (ccRCC) has shown durable responses to checkpoint blockade therapies. However, important gaps persist in the understanding of its immune microenvironment. This study ...aims to investigate the expression and prognostic significance of immune checkpoints in primary and metastatic ccRCC, in relation with mature dendritic cells (DC) and T-cell densities.
We investigated the infiltration and the localization of CD8(+) T cells and mature DC, and the expression of immune checkpoints (PD-1, LAG-3, PD-L1, and PD-L2) in relation with prognosis, in 135 primary ccRCC tumors and 51 ccRCC lung metastases. RNA expression data for 496 primary ccRCC samples were used as confirmatory cohort.
We identify two groups of tumors with extensive CD8(+) T-cell infiltrates. One group, characterized by high expression of immune checkpoints in the absence of fully functional mature DC, is associated with increased risk of disease progression. The second group, characterized by low expression of immune checkpoints and localization of mature DC in peritumoral immune aggregates (tertiary lymphoid structures), is associated with good prognosis.
The expression of the immune checkpoints and the localization of DC in the tumor microenvironment modulate the clinical impact of CD8(+) T cells in ccRCC.
Solid tumors, beyond mere accumulation of cancer cells, form a complex ecosystem consisting of normal epithelial cells, fibroblasts, blood and lymphatic vessels, structural components, and ...infiltrating hematopoietic cells including myeloid and lymphoid elements that impact tumor growth, tumor spreading, and clinical outcome. The composition of the immune microenvironment is diverse, including various populations of T cells, B cells, dendritic cells, natural killer cells, myeloid-derived suppressor cells, neutrophils, or macrophages. The immune contexture describes the density, location, and organization of these immune cells within solid tumors. In lung cancer, which is the deadliest type of cancer, and particularly in non-small cell lung cancer, its most prevalent form, reports have described some of the interactions between the tumor and the host. These data, in addition to articles on various types of tumors, provide a greater understanding of the tumor-host microenvironment interaction and stimulate the development of prognostic and predictive biomarkers, the identification of novel target antigens for therapeutic intervention, and the implementation of tools for long-term management of patients with cancer.
Background Hypothesizing that morphometric measurements are reliable markers of fitness in patients with lung cancer requiring aggressive surgical intervention, the purpose of this study was to ...assess their impact on postoperative outcome and long-term survival in patients with non-small cell lung cancer (NSCLC) requiring pneumonectomy. Methods Height, weight, and body mass index (BMI), as well as usual clinical, laboratory (including C-reactive protein CRP concentrations), and pathologic data were retrospectively retrieved from files of 161 consecutive patients treated by pneumonectomy for NSCLC, whose preoperative computed tomographic (CT) scans were available in the Picture Archive and Communication System (PACS) of the hospital. Cross-sectional areas of right and left psoas areas (measured by CT scan at the L3 level), perirenal fat thickness, and anterior subcutaneous tissue thickness at the left renal vein level were also assessed. Results BMI and total psoas area were strongly and directly correlated ( p = 0.0000001), whereas BMI was inversely related to CRP levels. Sarcopenia (total psoas area ≤33rd percentile) was associated with high CRP levels (>20 mg/L) ( p = 0.010). Factors associated with 90-day mortality included older age ( p = 0.000045), lower body weight ( p = 0.032), and BMI less than or equal to 25 kg/m2 ( p = 0.013). At univariate analysis, long-term outcome was negatively affected by a nonsquamous cell histologic type ( p = 0.011), pathologic stage IIIB–IV ( p =0.026), CRP levels greater than 20 mg/L ( p = 0.017), BMI less than or equal to 25 kg/m2 ( p = 0.010), and total psoas area less than or equal to the 33rd percentile ( p = 0.029). Multivariate analysis showed the independent prognostic value of both BMI and total psoas area. Conclusions BMI less than or equal to 25 kg/m2 and total psoas cross-sectional area less than or equal to the 33rd percentile are prognostic determinants in patients with NSCLC requiring pneumonectomy.
The mutational landscape of gray zone lymphoma (GZL) has not yet been established, and differences from related entities are largely unknown. Here, we studied coding sequence mutations of 50 ...Epstein-Barr virus (EBV)-negative GZLs and 20 polymorphic EBV+ diffuse large B-cell lymphoma (DLBCL) not otherwise specified (poly-EBV-L) in comparison with classical Hodgkin lymphoma (cHL), primary mediastinal large B-cell lymphoma (PMBCL), and DLBCL. Exomes of 21 GZL and 7 poly-EBV-L cases, along with paired constitutional DNA, were analyzed as a discovery cohort, followed by targeted sequencing of 217 genes in an extension cohort of 29 GZL and 13 poly-EBV-L cases. GZL cases with thymic niche involvement (anterior mediastinal mass) exhibited a mutation profile closely resembling cHL and PMBCL, with SOCS1 (45%), B2M (45%), TNFAIP3 (35%), GNA13 (35%), LRRN3 (32%), and NFKBIA (29%) being the most recurrently mutated genes. In contrast, GZL cases without thymic niche involvement (n = 18) had a significantly distinct pattern that was enriched in mutations related to apoptosis defects (TP53 39%, BCL2 28%, BIRC6 22%) and depleted in GNA13, XPO1, or NF-κB signaling pathway mutations (TNFAIP3, NFKBIE, IKBKB, NFKBIA). They also exhibited more BCL2/BCL6 rearrangements compared with thymic GZL. Poly-EBV-L cases presented a distinct mutational profile, including STAT3 mutations and a significantly lower coding mutation load in comparison with EBV− GZL. Our study highlights characteristic mutational patterns in GZL associated with presentation in the thymic niche, suggesting a common cell of origin and disease evolution overlapping with related anterior mediastinal lymphomas.
•The mutational landscape of GZL in the thymic niche resembles that of EBV− cHL and PMBCL, suggesting a shared cell of origin.•GZLs occurring outside of the thymic niche have a distinct mutational profile, with a subset of cases carrying TP53 and BCL2 mutations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Both the innate and adaptive immune systems contribute to tumor immunosurveillance in mice and humans; however, there is a paucity of direct evidence of a role for natural killer (NK) cells in this ...important process. In this study, we investigated the intratumoral phenotypic profile and functions of NK cells in primary human tumor specimens of non-small cell lung carcinoma (NSCLC). We used in situ methods to quantify and localize NK cells using the NKp46 marker and we characterized their phenotype in blood, tumoral, and nontumoral samples of NSCLC patients. Intratumoral NK cells displayed a profound and coordinated alteration of their phenotype, with a drastic reduction of NK cell receptor expression specifically detected in the tumoral region. According to their altered phenotype, intratumoral NK cells exhibited profound defects in the ability to activate degranulation and IFN-γ production. We found that the presence of NK cells did not impact the clinical outcome of patients with NSCLC. Finally, we showed that tumor cells heterogeneously express ligands for both activating and inhibitory NK receptors. Taken together, our results suggest that the NSCLC tumor microenvironment locally impairs NK cells, rendering them less tumorcidal and thereby supportive to cancer progression.
The 18-gene tumor inflammation signature (TIS) is a clinical research assay that enriches for clinical benefit to immune checkpoint blockade. We evaluated its ability to predict clinical benefit of ...immunotherapy in cancer patients treated with PD-1 checkpoint inhibitors in routine clinical care.
The CERTIM cohort is a prospective cohort which includes patients receiving immune checkpoint inhibitors in Cochin University hospital. RNA extracted from 58 archival formalin fixed paraffin embedded tumor blocks (including 38 lung cancers, 5 melanomas, 10 renal carcinomas, 4 urothelial carcinomas and 1 colon carcinoma) was hybridized to a beta version of the NanoString
PanCancer IO360™ CodeSet using nCounter
technology. Gene expression signatures were correlated with tumor responses (by RECIST criteria) and overall survival. PD-L1 immunostaining on tumor cells was assessed in 37 non-small cell lung cancer (NSCLC) samples and tumor mutational burden (TMB) measured by whole exome sequencing in 19 of these.
TIS scores were significantly associated with complete or partial response to anti-PD-1 treatment in the whole cohort (odds ratio = 2.64, 95% CI 1.4; 6.0, p = 0.008), as well as in the NSCLC population (odds ratio = 3.27, 95% CI 1.2; 11.6, p = 0.03). Patients whose tumor had a high TIS score (upper tertile) showed prolonged overall survival compared to patients whose tumor had lower TIS scores, both in the whole cohort (hazard ratio = 0.37, 95% CI 0.18, 0.76, p = 0.005) and in the NSCLC population (hazard ratio = 0.36, 95% CI 0.14, 0.90, p = 0.02). In the latter, the TIS score was independent from either PD-L1 staining on tumor cells (spearman coefficient 0.2) and TMB (spearman coefficient - 0.2).
These results indicate that validated gene expression assay measuring the level of tumor microenvironment inflammation such as TIS, are accurate and independent predictive biomarkers and can be easily implemented in the clinical practice.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
If immune cells are involved in tumor surveillance and have a prognostic impact in most primary tumors, little is known about their significance in metastases. Because patients' survival is ...heterogeneous, even at metastatic stages, we hypothesized that immune cells may be involved in the control of metastases. We therefore characterized the tumor immune microenvironment and its prognostic value in colorectal and renal cell carcinoma (RCC) metastases, and compared it to primary tumors.
We analyzed by immunohistochemistry (n = 192) and qPCR (n = 32) the immune environments of colorectal carcinoma and RCC lung metastases.
Metastases from colorectal carcinoma and RCC have different immune infiltrates. Higher densities of DC-LAMP(+) mature dendritic cells (P < 0.0001) and lower densities of NKp46(+) NK cells (P < 0.0001) were observed in colorectal carcinoma as compared to RCC metastases, whereas densities of T cells were similar. High densities of CD8(+) and DC-LAMP(+) cells correlated with longer overall survival (OS) in colorectal carcinoma (P = 0.008) and shorter OS in RCC (P < 0.0001). High NK-cell densities were associated with improved survival in RCC (P = 0.002) but not in colorectal carcinoma. Densities of immune cells correlated significantly from primary to relapsing metastases for the same patient. A TH1 orientation was found in colorectal carcinoma metastases, whereas a heterogeneous immune gene expression was found in RCC metastases.
Our results show a major prognostic value of the immune pattern (CD8(+)/DC-LAMP(+) cell densities) in colorectal carcinoma and RCC, reproducible from primary to metastatic tumors, although with opposite clinical impacts, and highlight the role of the tumor cell in shaping its immune environment.
We aimed to characterise lymphoid neogenesis in bronchiectasis and cystic fibrosis (CF) lungs and to examine the role of bacterial infection.Lymphoid aggregates were examined using ...immunohistochemical staining and morphometric analysis in surgical lung sections obtained from nonsmokers and patients with bronchiectasis or CF. Sterile,
- or
-coated agarose beads were instilled intratracheally in mice. Kinetics of lymphoid neogenesis and chemokine expression were examined over 14 days.Lymphoid aggregates were scarce in human lungs of nonsmokers, but numerous peribronchial lymphoid aggregates containing B-lymphocytes, T-lymphocytes, germinal centres and high endothelial venules were found in bronchiectasis and CF. Mouse lungs contained no lymphoid aggregate at baseline. During persistent
or
airway infection peribronchial lymphoid neogenesis occurred. At day 14 after instillation, lymphoid aggregates expressed markers of tertiary lymphoid organs and the chemokines CXCL12 and CXCL13. The airway epithelium was an important site of CXCL12, CXCL13 and interleukin-17A expression, which began at day 1 after instillation.Peribronchial tertiary lymphoid organs are present in bronchiectasis and in CF, and persistent bacterial infection triggered peribronchial lymphoid neogenesis in mice. Peribronchial localisation of tertiary lymphoid organs and epithelial expression of chemokines suggest roles for airway epithelium in lymphoid neogenesis.
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