Tumor-specific CD4 T cells cooperate with myeloid cells to remodel the pancreatic tumor microenvironment and enable effective immunotherapy
We interrogate antigen-specific CD4 T cells during immunotherapy in pancreatic ductal adenocarcinoma. Vaccination with MHC-II-restricted tumor epitopes impart superior protection compared to an immunodominant MHC-I epitope, prompting development of MHC-II affinity-enhanced tetramers to track tumor-specific CD4 T cells. As tumors progress, tumor-specific CD4 T cells decline, and remaining cells…
Pancreatic ductal adenocarcinoma patients who receive immunotherapy with MHC-II-restricted tumor epitopes show superior protection compared to those with immunodominant MHC-I epitopes. This has led to the development of MHC-II affinity-enhanced tetramers to track tumor-specific CD4 T cells. As the tumors progress, tumor-specific CD4 T cells decline and acquire regulatory features.
Agonistic anti-CD40 increases Th1 cell clonal expansion and temporarily decreases Tregs, while anti-PD-L1 promotes Tfh clonal expansion and tumor presence, preventing Treg rebound after anti-CD40 treatment. Treatment with anti-CD40 promotes intratumoral Stat1+ macrophages, tertiary lymphoid structures, and immune triads in tumors.
The presence of MHC-II on myeloid cells, but not B cells, is essential for immunotherapy-induced tertiary lymphoid structure formation and antitumor effects. The IL-15 complex enhances immunotherapy-induced Th1 effectors without promoting Tregs. Human immunotherapy transcriptomics reveals that effective response in patients is characterized by conserved Th1 programming and Treg destabilization.
In conclusion, tumor-specific CD4 T cells play a central role in the effectiveness of immunotherapy in solid tumors.
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