T cell–inflamed versus non-T cell–inflamed tumors: a conceptual framework for cancer immunotherapy drug
Posted: Mon Feb 03, 2020 7:59 pm
Abstract
Immunotherapies such as checkpoint blocking antibodies and adoptive cell transfer are emerging as treatments for a growing number of cancers. Despite clinical activity of immunotherapies across a range of cancer types, the majority of patients fail to respond to these treatments and resistance mechanisms remain incompletely defined. Responses to immunotherapy preferentially occur in tumors with a pre-existing antitumor T-cell response that can most robustly be measured via expression of dendritic cell and CD8+ T cell–associated genes. The tumor subset with high expression of this signature has been described as the T cell–”inflamed” phenotype. Segregating tumors by expression of the inflamed signature may help predict immunotherapy responsiveness. Understanding mechanisms of resistance in both the T cell–inflamed and non-inflamed subsets of tumors will be critical in overcoming treatment failure and expanding the proportion of patients responding to current immunotherapies. To maximize the impact of immunotherapy drug development, pretreatment stratification of targets associated with either the T cell–inflamed or non-inflamed tumor microenvironment should be employed. Similarly, biomarkers predictive of responsiveness to specific immune-modulatory therapies should guide therapy selection in a growing landscape of treatment options. Combination strategies may ultimately require converting non-T cell–inflamed tumors into T cell–inflamed tumors as a means to sensitize tumors to therapies dependent on T-cell killing.
The immune system can detect and eradicate cancer cells. However, tumors acquire genetic mutations, induce immunosuppressive signaling pathways and undergo epigenetic changes that lead to resistant phenotypes. This resistance manifests as a capacity to avoid immune recognition or disable antitumor components of immunity. At baseline, spontaneous antitumor T-cell response occurs in a fraction of patients with solid tumors. Although cancer in these patients continues to progress, the beneficial effect of antitumor immune engagement may persist during tumor progression. The biological processes associated with this spontaneous, though inadequate, induction of antitumor immunity correlate with improved clinical outcomes and may predict responsiveness to immunotherapy (1–3).
Across cancer, the majority of tumors lack a robust T-cell infiltrate prior to treatment. It is not clear why T cells infiltrate some tumors and not others. Fundamental to answering this question is a more thorough understanding of the essential events leading to a spontaneous antitumor T-cell response (Figure 1). Innate immune recognition of incipient neoplasms and activation of type I interferon (IFN) signaling are among the most proximal events required to generate a de novo T-cell responses (4,5). One major mediator of type I IFN generation is the cGAS/STING (stimulator of interferon genes) pathway, which is activated by cytosolic tumor-derived DNA. Activation of STING mediates innate immune sensing of cancer cells by tumor-infiltrating antigen-presenting cells (APC) (6). STING pathway activation in the tumor microenvironment leads to downstream type I IFN production, resulting in the recruitment and activation of dendritic cells, including the Batf3 (basic leucine zipper transcription factor ATF-like 3)-driven subset (4,7). In turn, Batf3-lineage dendritic cells cross-present tumor-derived antigen to CD8+ T cells and regulate T-cell recruitment to tumors (4,8). To eradicate cancer cells, CD8+ T cells must become appropriately activated, traffic to tumor tissue, overcome local mechanisms of immune suppression, and maintain their effector function.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145135/
Immunotherapies such as checkpoint blocking antibodies and adoptive cell transfer are emerging as treatments for a growing number of cancers. Despite clinical activity of immunotherapies across a range of cancer types, the majority of patients fail to respond to these treatments and resistance mechanisms remain incompletely defined. Responses to immunotherapy preferentially occur in tumors with a pre-existing antitumor T-cell response that can most robustly be measured via expression of dendritic cell and CD8+ T cell–associated genes. The tumor subset with high expression of this signature has been described as the T cell–”inflamed” phenotype. Segregating tumors by expression of the inflamed signature may help predict immunotherapy responsiveness. Understanding mechanisms of resistance in both the T cell–inflamed and non-inflamed subsets of tumors will be critical in overcoming treatment failure and expanding the proportion of patients responding to current immunotherapies. To maximize the impact of immunotherapy drug development, pretreatment stratification of targets associated with either the T cell–inflamed or non-inflamed tumor microenvironment should be employed. Similarly, biomarkers predictive of responsiveness to specific immune-modulatory therapies should guide therapy selection in a growing landscape of treatment options. Combination strategies may ultimately require converting non-T cell–inflamed tumors into T cell–inflamed tumors as a means to sensitize tumors to therapies dependent on T-cell killing.
The immune system can detect and eradicate cancer cells. However, tumors acquire genetic mutations, induce immunosuppressive signaling pathways and undergo epigenetic changes that lead to resistant phenotypes. This resistance manifests as a capacity to avoid immune recognition or disable antitumor components of immunity. At baseline, spontaneous antitumor T-cell response occurs in a fraction of patients with solid tumors. Although cancer in these patients continues to progress, the beneficial effect of antitumor immune engagement may persist during tumor progression. The biological processes associated with this spontaneous, though inadequate, induction of antitumor immunity correlate with improved clinical outcomes and may predict responsiveness to immunotherapy (1–3).
Across cancer, the majority of tumors lack a robust T-cell infiltrate prior to treatment. It is not clear why T cells infiltrate some tumors and not others. Fundamental to answering this question is a more thorough understanding of the essential events leading to a spontaneous antitumor T-cell response (Figure 1). Innate immune recognition of incipient neoplasms and activation of type I interferon (IFN) signaling are among the most proximal events required to generate a de novo T-cell responses (4,5). One major mediator of type I IFN generation is the cGAS/STING (stimulator of interferon genes) pathway, which is activated by cytosolic tumor-derived DNA. Activation of STING mediates innate immune sensing of cancer cells by tumor-infiltrating antigen-presenting cells (APC) (6). STING pathway activation in the tumor microenvironment leads to downstream type I IFN production, resulting in the recruitment and activation of dendritic cells, including the Batf3 (basic leucine zipper transcription factor ATF-like 3)-driven subset (4,7). In turn, Batf3-lineage dendritic cells cross-present tumor-derived antigen to CD8+ T cells and regulate T-cell recruitment to tumors (4,8). To eradicate cancer cells, CD8+ T cells must become appropriately activated, traffic to tumor tissue, overcome local mechanisms of immune suppression, and maintain their effector function.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145135/