Tumor and Host Factors Controlling Antitumor Immunity and Efficacy of Cancer Immunotherapy

Abstract

Despite recent clinical advances in immunotherapy, a fraction of cancer patients fails to respond to these interventions. Evidence from preclinical mouse models as well as clinical samples has provided evidence that the extent of activated T cell infiltration within the tumor microenvironment is associated with clinical response to immunotherapies including checkpoint blockade. Therefore, understanding the molecular mechanisms mediating the lack of T cell infiltration into the tumor microenvironment will be instrumental for the development of new therapeutic strategies to render those patients immunotherapy responsive. Recent data have suggested that major sources of intersubject heterogeneity include differences in somatic mutations in specific oncogene pathways between cancers of individual subjects and also environmental factors including commensal microbial composition. Successful identification of such causal factors should lead to new therapeutic approaches that may facilitate T cell entry into noninflamed tumors and expand the fraction of patients capable of responding to novel immunotherapies.

Keywords: Cancer immunotherapy; Microbiota; Tumor biology.

Figure 1

Processes involved in generation of the T cell-inflamed tumor microenvironment phenotype. Innate immune sensing of tumors appears to be dominantly mediated by the host STING pathway, which results in type I IFN production and activation of Batf3-lineage DCs. This DC subset cross-presents antigens to CD8⁺ T cells, which once activated can be recruited into the inflamed tumor microenvironment and contribute to tumor control. The same STING pathway engagement likely leads to production of CXCL9 and CXCL10, which are the key chemokines that support effector T cell recruitment.

Figure 2

Model for how tumor-intrinsic β-catenin signaling mediates exclusion of T cells from the tumor microenvironment. Activation of the β-catenin pathway in tumor cells results in induction of ATF3, which serves as a transcriptional repressor for CCL4 gene expression. Lack of CCL4 accounts for failed recruitment of CD103⁺ and CD8α⁺ DCs into the tumor microenvironment, thereby preventing cross-priming of host CD8⁺ T cells.

Figure 3

Potential mechanisms for Bifidobacterium-mediated improvement in antitumor immune responses. (A) and (B) A systemic factor might be released by Bifidobacterium (A) or by host cells, such as intestinal epithelial cells (B) that promotes global DC preactivation. (C) Altered DCs or DC precursors might be preactivated locally in the intestinal lamina propria and disseminate to distant sites. (D) A host cell, altered by crosstalk with Bifidobacterium, might interact with DCs to modulate DC function.