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.

Finding the right help in the tumor microenvironment

“…Physical interaction of PD-1 + ICOS + Th1 or Th17 cells with MHC II + DCs in the TME would likely enhance cross-priming of antitumor CD8 + T cells within the tumor-associated TLSs, allowing for local antitumor T cell repertoire expansion and diversification that is distinguishable from T cell priming in the periphery. It is intriguing that Duhen et al ( 11 ) report that the presence of stromally located DP CD4 + Th cells was strongly associated with CD39 + CD103 + CD8 + TIL (known to be enriched for tumor reactivity) content in the TME of HNSCC samples, but did not find such an association in CRC specimens. Differences in TME content of regulatory immune cells (i.e., Foxp3 + CD4 + Tregs and myeloid-derived suppressor cells) or tumor-intrinsic immune suppression mechanisms were not accounted for in these analyses and could therefore serve as potential mechanisms underlying the divergence in the immune cell interactions operating in the TME of HNSCC compared with that of CRC.…”

“…In this issue of the JCI , Duhen et al ( 11 ) profiled the tumor immune microenvironment in patients with HPV + head and neck squamous cell carcinoma (HNSCC) or microsatellite-stable colorectal carcinoma (CRC) and identified a subset of CD4 + Th cells coexpressing the immune checkpoint and costimulatory molecules programmed cell death 1 (PD-1) and ICOS. These double-positive (DP) cells were devoid of immune-suppressive activity and enriched in functional attributes associated with inflammatory T cell and humoral responses.…”

“…Based on tumor imaging data provided by Duhen et al, PD-1 + ICOS + CD4 + TILs and MHC II + antigen-presenting cells (APCs) were identified in close proximity within the tumor stroma ( 11 ). Such intercellular interactions may potentiate and sustain PD-1 + ICOS + CD4 + TILs.…”

“…Such intercellular interactions may potentiate and sustain PD-1 + ICOS + CD4 + TILs. Although Duhen and colleagues did not pedigree the Th-associated MHC II + APCs by characterizing surface markers, including ICOS ligand (ICOSL) ( 11 ), B cells and macrophages express the highest levels of ICOSL within the TME ( 12 ). Since ICOS-ICOSL interactions support tissue-resident memory development ( 13 ) and T follicular helper (Tfh) survival and function ( 14 ), B cells and macrophages may constitute the principal Th-associated APCs in tumors.…”

“…So how is this information instructive for improving response rates to interventional immunotherapies in the setting of HNSCC and CRC or other forms of solid cancer? As Duhen and authors note, their findings suggest the possibility of sorting functional DP CD4 + TILs from tumor biopsy material to provide an enriched source of nonexhausted, Treg-depleted, tumor antigen–specific T cells that could be expanded ex vivo for subsequent transfer back into the patient as an adoptive immunotherapy ( 11 , 16 , 17 ). Alternatively, TCRs cloned from DP CD4 + TILs reactive against patient-matched tumor (neo)antigens could be used to develop TCR-engineered T cells from the patient’s peripheral blood for adoptive transfer as an interventional therapy ( 16 , 17 ).…”