Format

Send to

Choose Destination
Cancer Immunol Immunother. 2019 Jul;68(7):1095-1106. doi: 10.1007/s00262-019-02346-4. Epub 2019 May 18.

Checkpoint blockade immunotherapy enhances the frequency and effector function of murine tumor-infiltrating T cells but does not alter TCRβ diversity.

Author information

1
Molecular Microbiology and Immunology Department, Saint Louis University School of Medicine, 1100 South Grand Blvd, St. Louis, MO, 63104, USA.
2
Alvin J. Siteman National Cancer Institute Comprehensive Cancer Center, St. Louis, MO, USA.
3
Molecular Microbiology and Immunology Department, Saint Louis University School of Medicine, 1100 South Grand Blvd, St. Louis, MO, 63104, USA. ryan.teague@health.slu.edu.
4
Alvin J. Siteman National Cancer Institute Comprehensive Cancer Center, St. Louis, MO, USA. ryan.teague@health.slu.edu.

Abstract

Checkpoint blockade immunotherapy is now a first-line treatment option for patients with melanoma. Despite achieving objective responses in about half of patients, the exact immune mechanisms elicited and those required for therapeutic success have not been clearly identified. Insight into these mechanisms is key for improving outcomes in a broader range of cancer patients. We used a murine melanoma model to track responses by different subsets of tumor-infiltrating lymphocytes (TIL) during checkpoint blockade immunotherapy. Tumors from treated mice had increased frequencies of both CD4+ and CD8+ T cells, which also showed evidence of functional reinvigoration and elevated effector cytokine production after immunotherapy. We predicted that increased T cell numbers and function within tumors reflected either infiltration by new T cells or clonal expansion by a few high-affinity tumor-reactive T cells. To address this, we compared TIL diversity before and after immunotherapy by sequencing the complementarity determining region 3 (CDR3) of all T cell receptor beta (TCRβ) genes. While checkpoint blockade effectively slowed tumor progression and increased T cell frequencies, the diversity of intratumoral T cells remained stable. This was true when analyzing total T cells and when focusing on smaller subsets of effector CD4+ and CD8+ TIL as well as regulatory T cells. Our study suggests that checkpoint blockade immunotherapy does not broaden the T cell repertoire within murine melanoma tumors, but rather expands existing T cell populations and enhances effector capabilities.

KEYWORDS:

Checkpoint blockade; Immunotherapy; Melanoma; T cell; TCR diversity

PMID:
31104075
DOI:
10.1007/s00262-019-02346-4
[Indexed for MEDLINE]

MeSH terms, Substances, Grant support

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Springer
Loading ...
Support Center