Impact of anatomic site on antigen-presenting cells in cancer

Abstract

Checkpoint blockade immunotherapy (CBT) can induce long-term clinical benefits in patients with advanced cancer; however, response rates to CBT vary by cancer type. Cancers of the skin, lung, and kidney are largely responsive to CBT, while cancers of the pancreas, ovary, breast, and metastatic lesions to the liver respond poorly. The impact of tissue-resident immune cells on antitumor immunity is an emerging area of investigation. Recent evidence indicates that antitumor immune responses and efficacy of CBT depend on the tissue site of the tumor lesion. As myeloid cells are predominantly tissue-resident and can shape tumor-reactive T cell responses, it is conceivable that tissue-specific differences in their function underlie the tissue-site-dependent variability in CBT responses. Understanding the roles of tissue-specific myeloid cells in antitumor immunity can open new avenues for treatment design. In this review, we discuss the roles of tissue-specific antigen-presenting cells (APCs) in governing antitumor immune responses, with a particular focus on the contributions of tissue-specific dendritic cells. Using the framework of the Cancer-Immunity Cycle, we examine the contributions of tissue-specific APC in CBT-sensitive and CBT-resistant carcinomas, highlight how these cells can be therapeutically modulated, and identify gaps in knowledge that remain to be addressed.

Keywords: antigen presentation; dendritic cells; immune evation; inflammation; tumor microenvironment.

Figure 1

Tissue-specific myeloid cell composition impacts antitumor immunity. Left, Productive antitumor immunity depends on the presence of stimulatory myeloid cells, such as cDC1, in the TME. cDC1 contributes to several critical functions, such as cross-presentation, antigen transport to the lymph node, T cell priming, and T cell recruitment, to drive tumor-reactive T cell responses. Right, Dysfunctional antitumor immunity can arise from tumors that are predominantly infiltrated by suppressive myeloid cells, such as M2 TAM and functionally impaired DC. cDC, conventional DC; DC, dendritic cell; pDC, plasmacytoid DC; TAM, tumor-associated macrophage; TME, tumor microenvironment.

Figure 2

The myeloid immune microenvironment varies depending on the tissue site of tumor origin. CBT-resistant carcinomas (pancreas, liver, ovary, and breast) are generally heavily infiltrated by suppressive myeloid cells, such as TAM and tolerogenic DC subsets, while stimulatory cDC1 are scarce and prone to becoming dysfunctional. CBT-sensitive carcinomas (lung, kidney) similarly harbor suppressive TAM and inhibitory DC, but they also contain protective stimulatory cDC1. The balance of immune-potentiating and immunosuppressive myeloid cells at each tissue site impacts antitumor immunity responses and sensitivity to CBT. CBT, checkpoint blockade immunotherapy; cDC, conventional DC; DC, dendritic cell; moDC, monocyte-derived DC; pDC, plasmacytoid DC; TAM, tumor-associated macrophage.