The immune system responds to cancer in two main ways. First, there are prewired responses involving myeloid cells, innate lymphocytes and innate-like adaptive lymphocytes that either reside in ...premalignant tissues or migrate directly to tumours, and second, there are antigen priming-dependent responses, in which adaptive lymphocytes are primed in secondary lymphoid organs before homing to tumours. Transforming growth factor-β (TGFβ) - one of the most potent and pleiotropic regulatory cytokines - controls almost every stage of the tumour-elicited immune response, from leukocyte development in primary lymphoid organs to their priming in secondary lymphoid organs and their effector functions in the tumour itself. The complexity of TGFβ-regulated immune cell circuitries, as well as the contextual roles of TGFβ signalling in cancer cells and tumour stromal cells, necessitates the use of rigorous experimental systems that closely recapitulate human cancer, such as autochthonous tumour models, to uncover the underlying immunobiology. The diverse functions of TGFβ in healthy tissues further complicate the search for effective and safe cancer therapeutics targeting the TGFβ pathway. Here we discuss the contextual complexity of TGFβ signalling in tumour-elicited immune responses and explain how understanding this may guide the development of mechanism-based cancer immunotherapy.
Metastasis remains the main reason for renal cell carcinoma (RCC)-associated mortality. Tyrosine kinase inhibitors (TKI) impart clinical benefit for most patients with RCC, but the determinants of ...response are poorly understood. We report an integrated genomic and transcriptomic analysis of patients with metastatic clear cell RCC (ccRCC) treated with TKI therapy and identify predictors of response. Patients in the COMPARZ phase III trial received first-line sunitinib or pazopanib with comparable efficacy. RNA-based analyses revealed four distinct molecular subgroups associated with response and survival. Characterization of these subgroups identified mutation profiles, angiogenesis, and macrophage infiltration programs to be powerful predictors of outcome with TKI therapy. Notably, predictors differed by the type of TKI received. Our study emphasizes the clinical significance of angiogenesis and immune tumor microenvironment and suggests that the critical effects its various aspects have on TKI efficacy vary by agent. This has broad implications for optimizing precision treatment of RCC. SIGNIFICANCE: The determinants of response to TKI therapy in metastatic ccRCC remain unknown. Our study demonstrates that key angiogenic and immune profiles of the tumor microenvironment may affect TKI response. These findings have the potential to inform treatment personalization in patients with RCC.
.
T lymphocytes’ ability to discriminate between structurally related antigens has been attributed to the unique signaling properties of the T cell receptor. However, recent studies have suggested that ...the output of this discrimination process is conditioned by environmental cues. Here, we demonstrate how the IL-2 cytokine, collectively generated by strongly activated T cell clones, can induce weaker T cell clones to proliferate. We identify the PI3K pathway as being critical for integrating the antigen and cytokine responses and for controlling cell-cycle entry. We build a hybrid stochastic/deterministic computational model that accounts for such signal synergism and demonstrates quantitatively how T cells tune their cell-cycle entry according to environmental cytokine cues. Our findings indicate that antigen discrimination by T cells is not solely an intrinsic cellular property but rather a product of integration of multiple cues, including local cues such as antigen quality and quantity, to global ones like the extracellular concentration of inflammatory cytokines.
Display omitted
•Strongly activated T cell clones induce weaker clones to proliferate through IL-2•IL-2-induced PI3K activation mediates the co-optation of weak T cell clones•A quantitative model shows how antigen and IL-2 signal additively to activate T cells•Co-optation is set by cell number, antigen load, and competition with T-reg cells
T cells integrate a wealth of signals to discriminate between structurally related antigens. Voisinne et al. demonstrate how IL-2, generated by neighboring strongly activated T cell clones, induces weaker clones to proliferate through the activation of PI3K, thus highlighting the collective nature of antigen discrimination by T cells.
VEGF inhibition enhanced the starvation-triggered cancer cell death and amplified the antitumour effect of 4T-Trap. ...targeted TGF-ß signalling blockade in helper T cells elicits an effective ...tissue-level cancer defence response that can provide a basis for therapies directed towards the cancer environment. With this mature vasculature phenotype, there was a sixfold increase of hypoxic areas adjacent to the dying tumour region (Extended Data Fig. 2d). ...the genetic abolition of TGF-ß signalling in CD4+ T cells is sufficient to trigger vasculature reorganization, leading to tumour hypoxia and cancer cell death. To test the therapeutic efficacy of 4TTrap in vivo, we generated a strain of transgenic mice expressing human CD4 (CD4 mice) using a bacterial artificial chromosome containing the human CD4 locus with the proximal enhancer region replaced by the mouse equivalent to augment its expression21 (Extended Data Fig. 4a). ...serum TGF-ß1 was depleted by 4T-Trap and TGF-ß-Trap, but not by mGO53 or anti-CD4, and the depletion kinetics matched their respective pharmacokinetics (Extended Data Fig. 5b, d).
The immune system uses two distinct defence strategies against infections: microbe-directed pathogen destruction characterized by type 1 immunity
, and host-directed pathogen containment exemplified ...by type 2 immunity in induction of tissue repair
. Similar to infectious diseases, cancer progresses with self-propagating cancer cells inflicting host-tissue damage. The immunological mechanisms of cancer cell destruction are well defined
, but whether immune-mediated cancer cell containment can be induced remains poorly understood. Here we show that depletion of transforming growth factor-β receptor 2 (TGFBR2) in CD4
T cells, but not CD8
T cells, halts cancer progression as a result of tissue healing and remodelling of the blood vasculature, causing cancer cell hypoxia and death in distant avascular regions. Notably, the host-directed protective response is dependent on the T helper 2 cytokine interleukin-4 (IL-4), but not the T helper 1 cytokine interferon-γ (IFN-γ). Thus, type 2 immunity can be mobilized as an effective tissue-level defence mechanism against cancer.
Malignancy can be suppressed by the immune system. However, the classes of immunosurveillance responses and their mode of tumor sensing remain incompletely understood. Here, we show that although ...clear cell renal cell carcinoma (ccRCC) was infiltrated by exhaustion-phenotype CD8
T cells that negatively correlated with patient prognosis, chromophobe RCC (chRCC) had abundant infiltration of granzyme A-expressing intraepithelial type 1 innate lymphoid cells (ILC1s) that positively associated with patient survival. Interleukin-15 (IL-15) promoted ILC1 granzyme A expression and cytotoxicity, and IL-15 expression in chRCC tumor tissue positively tracked with the ILC1 response. An ILC1 gene signature also predicted survival of a subset of breast cancer patients in association with IL-15 expression. Notably, ILC1s directly interacted with cancer cells, and IL-15 produced by cancer cells supported the expansion and anti-tumor function of ILC1s in a murine breast cancer model. Thus, ILC1 sensing of cancer cell IL-15 defines an immunosurveillance mechanism of epithelial malignancies.
Clear cell renal cell carcinomas (ccRCCs) are highly immune infiltrated, but the effect of immune heterogeneity on clinical outcome in ccRCC has not been fully characterized. Here we perform paired ...single-cell RNA (scRNA) and T cell receptor (TCR) sequencing of 167,283 cells from multiple tumor regions, lymph node, normal kidney, and peripheral blood of two immune checkpoint blockade (ICB)-naïve and four ICB-treated patients to map the ccRCC immune landscape. We detect extensive heterogeneity within and between patients, with enrichment of CD8A+ tissue-resident T cells in a patient responsive to ICB and tumor-associated macrophages (TAMs) in a resistant patient. A TCR trajectory framework suggests distinct T cell differentiation pathways between patients responding and resistant to ICB. Finally, scRNA-derived signatures of tissue-resident T cells and TAMs are associated with response to ICB and targeted therapies across multiple independent cohorts. Our study establishes a multimodal interrogation of the cellular programs underlying therapeutic efficacy in ccRCC.
Display omitted
•Single-cell RNA-seq reveals the architecture of the ccRCC immune microenvironment•Multiregional immune phenotypes integrated with bulk RNA-seq and tumor pathology•TCR usage varies by phenotype and defines T cell differentiation trajectories•Signatures of tissue-resident T cells and TAMs predict clinical outcome
Krishna et al. dissect the immune microenvironment and TCR clonotype dynamics in multiregional clear cell renal cell carcinoma (ccRCC) samples at single-cell resolution. They show that CD8+ tissue-resident T cells and distinct tumor-associated macrophage (TAM) populations are associated with response and resistance to immune checkpoint blockade (ICB) in ccRCC.
In metazoan organisms, cell competition acts as a quality control mechanism to eliminate unfit cells in favour of their more robust neighbours
. This mechanism has the potential to be maladapted, ...promoting the selection of aggressive cancer cells
. Tumours are metabolically active and are populated by stroma cells
, but how environmental factors affect cancer cell competition remains largely unknown. Here we show that tumour-associated macrophages (TAMs) can be dietarily or genetically reprogrammed to outcompete MYC-overexpressing cancer cells. In a mouse model of breast cancer, MYC overexpression resulted in an mTORC1-dependent 'winner' cancer cell state. A low-protein diet inhibited mTORC1 signalling in cancer cells and reduced tumour growth, owing unexpectedly to activation of the transcription factors TFEB and TFE3 and mTORC1 in TAMs. Diet-derived cytosolic amino acids are sensed by Rag GTPases through the GTPase-activating proteins GATOR1 and FLCN to control Rag GTPase effectors including TFEB and TFE3
. Depletion of GATOR1 in TAMs suppressed the activation of TFEB, TFE3 and mTORC1 under the low-protein diet condition, causing accelerated tumour growth; conversely, depletion of FLCN or Rag GTPases in TAMs activated TFEB, TFE3 and mTORC1 under the normal protein diet condition, causing decelerated tumour growth. Furthermore, mTORC1 hyperactivation in TAMs and cancer cells and their competitive fitness were dependent on the endolysosomal engulfment regulator PIKfyve. Thus, noncanonical engulfment-mediated Rag GTPase-independent mTORC1 signalling in TAMs controls competition between TAMs and cancer cells, which defines a novel innate immune tumour suppression pathway that could be targeted for cancer therapy.
Tumors are populated by antigen-presenting cells (APCs) including macrophage subsets with distinct origins and functions. Here, we examined how cancer impacts mononuclear phagocytic APCs in a murine ...model of breast cancer. Tumors induced the expansion of monocyte-derived tumor-associated macrophages (TAMs) and the activation of type 1 dendritic cells (DC1s), both of which expressed and required the transcription factor interferon regulatory factor-8 (IRF8). Although DC1s mediated cytotoxic T lymphocyte (CTL) priming in tumor-draining lymph nodes, TAMs promoted CTL exhaustion in the tumor, and IRF8 was required for TAMs’ ability to present cancer cell antigens. TAM-specific IRF8 deletion prevented exhaustion of cancer-cell-reactive CTLs and suppressed tumor growth. Tumors from patients with immune-infiltrated renal cell carcinoma had abundant TAMs that expressed IRF8 and were enriched for an IRF8 gene expression signature. Furthermore, the TAM-IRF8 signature co-segregated with CTL exhaustion signatures across multiple cancer types. Thus, CTL exhaustion is promoted by TAMs via IRF8.
Display omitted
•IRF8-expressing TAMs present cancer cell antigens and drive CTL exhaustion•MafBiCreIrf8flPyMT mice lose TAM antigen presentation, gain anti-tumor CTL response•TAMs from human cancer patients express IRF8 and an IRF8-dependent gene program•A TAM-IRF8 gene signature tracks with CTL exhaustion in multiple human malignancies
Macrophages of distinct origin and function populate tumors. Nixon et al. examine how cancer impacts mononuclear phagocytic antigen-presenting cells and find that monocyte-derived tumor-associated macrophages (TAMs) present cancer cell antigens and drive cytotoxic T cell exhaustion, promoting tumor growth in a manner dependent on the transcription factor IRF8.
Peripheral T cell tolerance is promoted by the regulatory cytokine TGF-β and Foxp3-expressing Treg cells. However, whether TGF-β and Treg cells are part of the same regulatory module, or exist ...largely as distinct pathways to repress self-reactive T cells remains incompletely understood. Using a transgenic model of autoimmune diabetes, here we show that ablation of TGF-β receptor II (TβRII) in T cells, but not Foxp3 deficiency, resulted in early-onset diabetes with complete penetrance. The rampant autoimmune disease was associated with enhanced T cell priming and elevated T cell expression of the inflammatory cytokine GM-CSF, concomitant with pancreatic infiltration of inflammatory monocytes that triggered immunopathology. Ablation of the GM-CSF receptor alleviated the monocyte response and inhibited disease development. These findings reveal that TGF-β promotes T cell tolerance primarily via Foxp3-independent mechanisms and prevents autoimmunity in this model by repressing the cross talk between adaptive and innate immune systems.
PDF
