Chemotherapy has historically been the mainstay of cancer treatment, but our understanding of what drives a successful therapeutic response remains limited. The diverse response of cancer patients to ...chemotherapy has been attributed principally to differences in the proliferation rate of the tumor cells, but there is actually very little experimental data supporting this hypothesis. Instead, other mechanisms at the cellular level and the composition of the tumor microenvironment appear to drive chemotherapy sensitivity. In particular, the immune system is a critical determinant of chemotherapy response with the depletion or knock-out of key immune cell populations or immunological mediators completely abrogating the benefits of chemotherapy in pre-clinical models. In this perspective, we review the literature regarding the known mechanisms of action of cytotoxic chemotherapy agents and the determinants of response to chemotherapy from the level of individual cells to the composition of the tumor microenvironment. We then summarize current work toward the development of dynamic biomarkers for response and propose a model for a chemotherapy sensitive tumor microenvironment.
Abstract
The biological determinants of the response to immune checkpoint blockade (ICB) in cancer remain incompletely understood. Little is known about dynamic biological events that underpin ...therapeutic efficacy due to the inability to frequently sample tumours in patients. Here, we map the transcriptional profiles of 144 responding and non-responding tumours within two mouse models at four time points during ICB. We find that responding tumours display on/fast-off kinetics of type-I-interferon (IFN) signaling. Phenocopying of this kinetics using time-dependent sequential dosing of recombinant IFNs and neutralizing antibodies markedly improves ICB efficacy, but only when IFNβ is targeted, not IFNα. We identify Ly6C
+
/CD11b
+
inflammatory monocytes as the primary source of IFNβ and find that active type-I-IFN signaling in tumour-infiltrating inflammatory monocytes is associated with T cell expansion in patients treated with ICB. Together, our results suggest that on/fast-off modulation of IFNβ signaling is critical to the therapeutic response to ICB, which can be exploited to drive clinical outcomes towards response.
What is Kindness in Science and why does it matter? Boulter, Jessica; Orozco Morales, Mariana Lizeth; Principe, Nicola ...
Immunology and cell biology,
February 2023, Volume:
101, Issue:
2
Journal Article
Peer reviewed
Open access
Kindness in Science is a grassroots initiative to establish a scientific community built on diversity, respect and well‐being, which would ultimately lead to happier scientists and better scientific ...outcomes. We believe that the key areas that we can become kinder as scientists include yourself, each other, the environment and the wider community. Here, we discuss the key barriers to kindness in each of these areas, and ways we can overcome these issues to create kinder, more sustainable and harmonious research teams.
Immune checkpoint therapy (ICT) results in durable responses in individuals with some cancers, but not all patients respond to treatment. ICT improves CD8
cytotoxic T lymphocyte (CTL) function, but ...changes in tumor antigen-specific CTLs post-ICT that correlate with successful responses have not been well characterized. Here, we studied murine tumor models with dichotomous responses to ICT. We tracked tumor antigen-specific CTL frequencies and phenotype before and after ICT in responding and non-responding animals. Tumor antigen-specific CTLs increased within tumor and draining lymph nodes after ICT, and exhibited an effector memory-like phenotype, expressing IL-7R (CD127), KLRG1, T-bet, and granzyme B. Responding tumors exhibited higher infiltration of effector memory tumor antigen-specific CTLs, but lower frequencies of regulatory T cells compared to non-responders. Tumor antigen-specific CTLs persisted in responding animals and formed memory responses against tumor antigens. Our results suggest that increased effector memory tumor antigen-specific CTLs, in the presence of reduced immunosuppression within tumors is part of a successful ICT response. Temporal and nuanced analysis of T cell subsets provides a potential new source of immune based biomarkers for response to ICT.
Chemotherapy is included in treatment regimens for many solid cancers, but when administered as a single agent it is rarely curative. The addition of immune checkpoint therapy to standard ...chemotherapy regimens has improved response rates and increased survival in some cancers. However, most patients do not respond to treatment and immune checkpoint therapy can cause severe side effects. Therefore, there is a need for alternative immunomodulatory drugs that enhance chemotherapy.
We used gene expression data from cyclophosphamide (CY) responders and non-responders to identify existing clinically approved drugs that could phenocopy a chemosensitive tumor microenvironment (TME), and tested combination treatments in multiple murine cancer models.
The vitamin A derivative tretinoin was the top predicted upstream regulator of response to CY. Tretinoin pre-treatment induced an inflammatory, interferon-associated TME, with increased infiltration of CD8 + T cells, sensitizing the tumor to subsequent chemotherapy. However, while combination treatment significantly improved survival and cure rate in a CD4
and CD8
T cell dependent manner in AB1-HA murine mesothelioma, this effect was model-selective, and could not be replicated using other cell lines.
Despite the promising data in one model, the inability to validate the efficacy of combination treatment in multiple cancer models deprioritizes tretinoin/cyclophosphamide combination therapy for clinical translation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The use of lipid nanoparticles (LNP) to encapsulate and deliver mRNA has become an important therapeutic advance. In addition to vaccines, LNP-mRNA can be used in many other applications. For ...example, targeting the LNP with anti-CD5 antibodies (CD5/tLNP) can allow for efficient delivery of mRNA payloads to T cells to express protein. As the percentage of protein expressing T cells induced by an intravenous injection of CD5/tLNP is relatively low (4-20%), our goal was to find ways to increase mRNA-induced translation efficiency. We showed that T cell activation using an anti-CD3 antibody improved protein expression after CD5/tLNP transfection in vitro but not in vivo. T cell health and activation can be increased with cytokines, therefore, using mCherry mRNA as a reporter, we found that culturing either mouse or human T cells with the cytokine IL7 significantly improved protein expression of delivered mRNA in both CD4
and CD8
T cells in vitro. By pre-treating mice with systemic IL7 followed by tLNP administration, we observed significantly increased mCherry protein expression by T cells in vivo. Transcriptomic analysis of mouse T cells treated with IL7 in vitro revealed enhanced genomic pathways associated with protein translation. Improved translational ability was demonstrated by showing increased levels of protein expression after electroporation with mCherry mRNA in T cells cultured in the presence of IL7, but not with IL2 or IL15. These data show that IL7 selectively increases protein translation in T cells, and this property can be used to improve expression of tLNP-delivered mRNA in vivo.
With immune checkpoint therapy (ICT) having reshaped the treatment of many cancers, the next frontier is to identify and develop novel combination therapies to improve efficacy. Previously, we and ...others identified beneficial immunological effects of the vitamin A derivative tretinoin on anti-tumour immunity. Although it is known that tretinoin preferentially depletes myeloid derived suppressor cells in blood, little is known about the effects of tretinoin on the tumour microenvironment, hampering the rational design of clinical trials using tretinoin in combination with ICT. Here, we aimed to identify how tretinoin changed the tumour microenvironment in mouse tumour models, using flow cytometry and RNAseq, and we sought to use that information to establish optimal dosing and scheduling of tretinoin in combination with several ICT antibodies in multiple cancer models. We found that tretinoin rapidly induced an interferon dominated inflammatory tumour microenvironment, characterised by increased CD8+ T cell infiltration. This phenotype completely overlapped with the phenotype that was induced by ICT itself, and we confirmed that the combination further amplified this inflammatory milieu. The addition of tretinoin significantly improved the efficacy of anti-CTLA4/anti-PD-L1 combination therapy, and staggered scheduling was more efficacious than concomitant scheduling, in a dose-dependent manner. The positive effects of tretinoin could be extended to ICT antibodies targeting OX40, GITR and CTLA4 monotherapy in multiple cancer models. These data show that tretinoin induces an interferon driven, CD8+ T cell tumour microenvironment that is responsive to ICT.
Antibodies that target immune checkpoints such as cytotoxic T lymphocyte antigen 4 (CTLA-4) and the programmed cell death protein 1/ligand 1 (PD-1/PD-L1) are now a treatment option for multiple ...cancer types. However, as a monotherapy, objective responses only occur in a minority of patients. Chemotherapy is widely used in combination with immune checkpoint blockade (ICB). Although a variety of isolated immunostimulatory effects have been reported for several classes of chemotherapeutics, it is unclear which chemotherapeutics provide the most benefit when combined with ICB. We investigated 10 chemotherapies from the main canonical classes dosed at the clinically relevant maximum tolerated dose in combination with anti-CTLA-4/anti-PD-L1 ICB. We screened these chemo-immunotherapy combinations in two murine mesothelioma models from two different genetic backgrounds, and identified chemotherapies that produced additive, neutral or antagonistic effects when combined with ICB. Using flow cytometry and bulk RNAseq, we characterized the tumor immune milieu in additive chemo-immunotherapy combinations. 5-fluorouracil (5-FU) or cisplatin were additive when combined with ICB while vinorelbine and etoposide provided no additional benefit when combined with ICB. The combination of 5-FU with ICB augmented an inflammatory tumor microenvironment with markedly increased CD8
T cell activation and upregulation of IFNγ, TNFα and IL-1β signaling. The effective anti-tumor immune response of 5-FU chemo-immunotherapy was dependent on CD8
T cells but was unaffected when TNFα or IL-1β cytokine signaling pathways were blocked. Our study identified additive and non-additive chemotherapy/ICB combinations and suggests a possible role for increased inflammation in the tumor microenvironment as a basis for effective combination therapy.
Time-critical transcriptional events in the immune microenvironment are important for response to immune checkpoint blockade (ICB), yet these events are difficult to characterise and remain ...incompletely understood. Here, we present whole tumor RNA sequencing data in the context of treatment with ICB in murine models of AB1 mesothelioma and Renca renal cell cancer. We sequenced 144 bulk RNAseq samples from these two cancer types across 4 time points prior and after treatment with ICB. We also performed single-cell sequencing on 12 samples of AB1 and Renca tumors an hour before ICB administration. Our samples were equally distributed between responders and non-responders to treatment. Additionally, we sequenced AB1-HA mesothelioma tumors treated with two sample dissociation protocols to assess the impact of these protocols on the quality transcriptional information in our samples. These datasets provide time-course information to transcriptionally characterize the ICB response and provide detailed information at the single-cell level of the early tumor microenvironment prior to ICB therapy.
While chemotherapy remains the first-line treatment for many cancers, it is still unclear what distinguishes responders from non-responders. Here, we characterize the chemotherapy-responsive tumor ...microenvironment in mice, using RNA sequencing on tumors before and after cyclophosphamide, and compare the gene expression profiles of responders with progressors. Responsive tumors have an inflammatory and highly immune infiltrated pre-treatment tumor microenvironment characterized by the enrichment of pathways associated with CD4+ T cells, interferons (IFNs), and tumor necrosis factor alpha (TNF-α). The same gene expression profile is associated with response to cyclophosphamide-based chemotherapy in patients with breast cancer. Finally, we demonstrate that tumors can be sensitized to cyclophosphamide and 5-FU chemotherapy by pre-treatment with recombinant TNF-α, IFNγ, and poly(I:C). Thus, a CD4+ T cell-inflamed pre-treatment tumor microenvironment is necessary for response to chemotherapy, and this state can be therapeutically attained by targeted immunotherapy.
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•Cyclophosphamide-responsive tumors are inflammatory and highly immune infiltrated•The response to cyclophosphamide is dependent on CD4 T cells and IFNγ•Sensitizing a tumor using targeted immunotherapy improves chemotherapy efficacy
Tilsed et al. characterize the tumor microenvironment associated with response to cyclophosphamide chemotherapy. They find that a CD4 T cell associated inflammatory IFN/TNF-α gene signature is associated with response in a murine mesothelioma model and patients with breast cancer. Furthermore, chemotherapy efficacy can be improved by pre-treating tumors with targeted immunotherapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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