PD-1 and ICOS coexpression identifies tumor-reactive CD4+ T cells in human solid tumors
Rebekka Duhen, Olivier Fesneau, Kimberly A. Samson, Alexandra K. Frye, Michael Beymer, Venkatesh Rajamanickam, David Ross, Eric Tran, Brady Bernard, Andrew D. Weinberg, Thomas Duhen
Rebekka Duhen, Olivier Fesneau, Kimberly A. Samson, Alexandra K. Frye, Michael Beymer, Venkatesh Rajamanickam, David Ross, Eric Tran, Brady Bernard, Andrew D. Weinberg, Thomas Duhen
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Research Article Immunology Oncology

PD-1 and ICOS coexpression identifies tumor-reactive CD4+ T cells in human solid tumors

Abstract

CD4+ Th cells play a key role in orchestrating immune responses, but the identity of the CD4+ Th cells involved in the antitumor immune response remains to be defined. We analyzed the immune cell infiltrates of head and neck squamous cell carcinoma and colorectal cancers and identified a subset of CD4+ Th cells distinct from FOXP3+ Tregs that coexpressed programmed cell death 1 (PD-1) and ICOS. These tumor-infiltrating lymphocyte CD4+ Th cells (CD4+ Th TILs) had a tissue-resident memory phenotype, were present in MHC class II–rich areas, and proliferated in the tumor, suggesting local antigen recognition. The T cell receptor repertoire of the PD-1+ICOS+ CD4+ Th TILs was oligoclonal, with T cell clones expanded in the tumor, but present at low frequencies in the periphery. Finally, these PD-1+ICOS+ CD4+ Th TILs were shown to recognize both tumor-associated antigens and tumor-specific neoantigens. Our findings provide an approach for isolating tumor-reactive CD4+ Th TILs directly ex vivo that will help define their role in the antitumor immune response and potentially improve future adoptive T cell therapy approaches.

Authors

Rebekka Duhen, Olivier Fesneau, Kimberly A. Samson, Alexandra K. Frye, Michael Beymer, Venkatesh Rajamanickam, David Ross, Eric Tran, Brady Bernard, Andrew D. Weinberg, Thomas Duhen

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Figure 4

DP CD4+ Th cells are in the tumor stroma proximal to MHC class II+ cells.

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DP CD4+ Th cells are in the tumor stroma proximal to MHC class II+ cells...
mIHC for CD3, CD8, FOXP3, ICOS, MHC class II, and cytokeratin on FFPE tissue sections from HNSCC and CRC tumors. Representative ROIs (left) from an HNSCC tumor (A) and a CRC tumor (B) and the corresponding cellular spatial relationship maps (right). Scale bars: 200 μm. The maps show cytokeratin+ cells (tumor) in black, MHC class II+ cells in blue, and CD3+CD8–FOXP3–ICOS+ (DP CD4+ Th cells) in red. (C) Analysis of the distribution of CD3+CD8–FOXP3–ICOS+ (DP CD4+ Th cells) in the tumor stroma and tumor epithelium in 14 tumors (n = 8 HNSCC and n = 6 CRC). (D) Neighbor’s cell analysis was performed on 11 tumors (n = 6 HNSCC and n = 5 CRC). The proportion of MHC class II+ cells in the stroma and cytokeratin+ cells detected within a 15 μm radius from CD3+CD8–FOXP3–ICOS+ (DP CD4+ Th) cells is indicated as the frequency of total cells. Circles represent HNSCC tumors, and triangles represent CRC tumors. Horizontal lines indicate the mean ± SEM. Data for patients with MHC class II–expressing tumor cells are shown in red in D.