Tumor Cell-Intrinsic Factors Underlie Heterogeneity of Immune Cell Infiltration and Response to Immunotherapy

Abstract

The biological and functional heterogeneity between tumors-both across and within cancer types-poses a challenge for immunotherapy. To understand the factors underlying tumor immune heterogeneity and immunotherapy sensitivity, we established a library of congenic tumor cell clones from an autochthonous mouse model of pancreatic adenocarcinoma. These clones generated tumors that recapitulated T cell-inflamed and non-T-cell-inflamed tumor microenvironments upon implantation in immunocompetent mice, with distinct patterns of infiltration by immune cell subsets. Co-injecting tumor cell clones revealed the non-T-cell-inflamed phenotype is dominant and that both quantitative and qualitative features of intratumoral CD8 T cells determine response to therapy. Transcriptomic and epigenetic analyses revealed tumor-cell-intrinsic production of the chemokine CXCL1 as a determinant of the non-T-cell-inflamed microenvironment, and ablation of CXCL1 promoted T cell infiltration and sensitivity to a combination immunotherapy regimen. Thus, tumor cell-intrinsic factors shape the tumor immune microenvironment and influence the outcome of immunotherapy.

Interleukin‐33 activates and recruits natural killer cells to inhibit pulmonary metastatic cancer development

“…These conflicting results may due to the differences in the tumor‐bearing models used, as IL‐33 appears to work in an environment‐dependent manner. Accumulating evidence suggests that tumor cell‐intrinsic factors underlie the sensitivity of tumor cells to immunologic cytotoxicity . Thus, tumor‐bearing models involving different types of tumor cell may elicit entirely different outcomes.…”

“…Accumulating evidence suggests that tumor cell-intrinsic factors underlie the sensitivity of tumor cells to immunologic cytotoxicity. 44 Thus, tumor-bearing models involving different types of tumor cell may elicit entirely different outcomes. Indeed, in our study, NK cell deficiency completely abolished the IL-33-mediated inhibition of tumor development in 4T1-bearing mice, but not B16-F10-bearing mice.…”

Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation

“…Taken together, these studies raise the possibility that TP63 functions as an amplifier of NFkB transcriptional output to drive enhanced secretion of inflammatory mediators in squamous subtype PDA tumors. In addition to IL-1α, TP63 promotes expression of other pro-inflammatory cytokines that have been implicated in the development and progression of PDA, such as CXCL1 and GM-CSF (Bayne et al, 2012;Li et al, 2018;Pylayeva-Gupta et al, 2012). Notably, both of these cytokines are also produced by iCAFs, suggesting that the pro-tumorigenic effects of these factors would be amplified by IL-1α-mediated crosstalk between TP63-expressing tumor cells and iCAFs.…”

Clonal replacement of tumor-specific T cells following PD-1 blockade

“…Second, the presence of novel clones suggests an alternative hypothesis for the improved activity of checkpoint blockade agents in immune-infiltrated ('hot') vs immune-desert ('cold') tumors. That is, perhaps the reason that 'hot' tumors respond to therapy is due to an intrinsic ability of the tumor to constantly attract new T cells 56 , rather than the presence of pre-existing T cells in the tumor. Therefore, therapeutic agents that improve recruitment or infiltration of T cells into the tumor might be sufficient to rescue therapeutic responses in cold tumors.…”