Finding the right help in the tumor microenvironment

Abstract

Tumor-infiltrating lymphocytes (TILs) contain substantial numbers of CD4+ T cells mediating pro- and antitumor functions. While CD4+ Tregs are well characterized and known to promote tumor immune evasion, the fingerprint of CD4+ Th cells that recognizes tumor antigens and serves to restrict disease progression has remained poorly discriminated. In this issue of the JCI, Duhen et al. analyzed tumors from patients with head and neck squamous cell carcinoma or colon carcinoma and identified a unique programmed cell death 1-positive, ICOS1-positive (PD-1+ICOS1+) subpopulation of CD4+ TILs highly enriched for the ability to recognize tumor-associated antigens. These cells localized proximally to MHC II+ antigen-presenting cells and CD8+ T cells within tumors, where they appeared to proliferate and function almost exclusively as Th cells. These potentially therapeutic Th cells can be monitored for patient prognosis and are expected to have substantial utility in developing personalized adoptive cell- and vaccine-based immunotherapeutic approaches for improving patient outcomes.

Figure 1. PD-1⁺ICOS⁺CD4⁺ TILs in HNSCC and CRC tumors are enriched for the tissue-resident memory cell phenotype and reactivity to tumor antigens.

Tumor-derived DP Th cells recognize cancer-relevant antigens, maintain polyfunctionality, and mediate primarily non-Treg functions in the TME. In the study by Duhen et al. (11), DP cells represented a substantial proportion of CD4⁺ TILs in HNSCC and CRC tumor specimens and were enriched in HPV-reactive Th cells (from HNSCC samples) and neoantigen-reactive Th cells (from HNSCC and CRC samples). Tumor-reactive Th cells included several functional subsets: Th1 (marked by TBET, IFNG), Th2 (marked by GATA3, IL13), Tfh (marked by BCL6, CXCL13, IL21), and Th17 (marked by RORC, IL17A). Within the stroma of the TME, DP CD4⁺ TILs were organized in lymphoid aggregates with MHC II⁺ APCs and CD8⁺ T cells reminiscent of immature TLSs. A DP CD4⁺ TIL status may provide a useful index for patients’ prognosis and response to interventional immunotherapy, with the isolated cells and targeted antigens serving as the basis for personalized adoptive cell therapies and patient-specific vaccines, respectively.