Abstract
Type 2 DCs (DC2s) comprise the majority of conventional DCs within most tumors; however, little is known about their ability to initiate and sustain antitumor immunity, as most studies have focused on antigen cross-presenting DC1s. Here, we report that DC2 infiltration identified by analysis of multiple human cancer data sets showed a significant correlation with survival across multiple human cancers, with the benefit being seen in tumors resistant to cytotoxic T cell control. Characterization of DC subtype infiltration into an immunotherapy-resistant model of breast cancer revealed that impairment of DC1s through 2 unique models resulted in enhanced DC2 functionality and improved tumor control. BATF3 deficiency depleted intratumoral DC1s, which led to increased DC2 lymph node migration and CD4+ T cell activation. Enhancing DC2 stimulatory potential by genetic deletion of Hsp90b1 (encoding molecular chaperon GP96) led to a similar enhancement of T cell immunity and improved survival in a spontaneous breast cancer model. These data highlight the therapeutic and prognostic potential of DC2s within checkpoint blockade–resistant tumors.
Highlights
Breakthroughs in understanding the roles of immune cells as active members of the complex tumor microenvironment have led to the development of revolutionary immunotherapies capable of inducing sustained remission in numerous cancer types [1]
We investigated the prognostic value of DC subtype gene signatures within human tumors and found that DC2 infiltration displayed a stronger correlation with survival in breast cancer patients than DC1, in highly suppressive subtypes
Our results suggest that empowering the DC2–CD4+ T cell axis may hold promise for treating breast cancers insensitive to cytotoxic T cells
Summary
Breakthroughs in understanding the roles of immune cells as active members of the complex tumor microenvironment have led to the development of revolutionary immunotherapies capable of inducing sustained remission in numerous cancer types [1]. Prime examples include the recently FDA-approved immune checkpoint blockade (ICB) and chimeric antigen receptor (CAR) T cell therapies that unleash potent cytotoxic T cells on tumors. In spite of their potential, favorable outcomes are currently achieved in only a minority of patients [2,3,4,5], underscoring the need to better understand the complex interactions between infiltrating immune cells and the tumor microenvironment. Cancer cells develop heterogeneous means to avoid immune clearance at multiple points during the tumor immunity cycle: tumor recognition, antigen trafficking, and effector cell activation/infiltration [9]. Successful immunotherapy for breast cancer will require identifying and targeting suppressor cells, as well as the upstream events that control their activity
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