The adaptive immune system comprises specialized cells and biochemical pathways that are designed to target and destroy pathogens and tumor cells. This is generally achieved by recognizing cells that express abnormal protein markers resulting from changes induced by invading organisms or tumor transformation.

The primary cell type involved in the destruction of infected or tumor cells are cytotoxic T cells.^[1] Immunotherapies involving the expansion and engineering of specialized cytotoxic T cells has been employed for nearly a decade.

In the case of tumor-cell targeting, the prevailing view among immunologists has been that individual T cells can only recognize one specific tumor antigen.^[2]  However, a new study on tumor infiltrating lymphocytes (TILs) suggests certain T cells may actually be capable of targeting multiple tumor antigens.

Study Background

Research conducted by a collaborative group from Herlev Hospital in Denmark and Cardiff University in the UK has uncovered the astonishing existence of single T cells capable of recognizing different tumor antigens.^[3]

The researchers wanted to understand the biological differences between patients with successful immunotherapy outcomes and those who did not clear cancers. The study involved a few patients who had stage IV melanoma and treated via tumor infiltrating lymphocyte therapy (TIL therapy).

TILs are tumor-penetrating T cells that recognize tumor cells as abnormal. For TIL therapy, TILs are collected from a surgically resected or biopsied tumor and expanded in the laboratory. The large number of TILs are then infused back into the patient.

Discovery of “Multiprong” T Cells

The study entailed analyzing the TIL infusion source of patients who achieved long-term remission of melanoma to determine the antigens targeted by the T cells. Proteomic technologies were used to identify cancer-related epitopes recognized by the T cells.^[4]

T cell clones within the TIL infusion product were found to respond to three different antigen epitopes simultaneously. Two of the discovered recognized epitopes are newly identified. The cancer-specific T cell receptors were found to persist years after the TIL therapy.

Also striking is that the tumor-associated antigen recognition was additive, resulting in superior tumor cell recognition compared to that of conventional T cells that only recognize one antigen. The observation that these “multiprong” T cells are not found in patients whose cancer progresses despite treatment suggests that these T cells are key to cancer clearance or remission.

Implications for Future Immunotherapies

Cancer cells can stop expressing an antigen recognized by conventional T cells,and this evading mechanism allows the cancer to continue to expand in a patient.^[5]

This biological advantage of cancer cells could be overcome by T cells that can recognize multiple cancer cell antigens. The discovery of individual T cells that can simultaneously recognize more than one tumor antigen can lead to the development of superior cancer-fighting tools for the oncologist.

The discovered multiprong T cells can recognize multiple epitopes on the surface of a cancer cell; therefore, immunotherapies based on multiprong T cells can increase the efficacy of cancer-clearing therapies. These cells could also enhance the ability to design treatments that can target different types of cancers.

Given the small number of patients in the reported study, one with a larger number of TIL-treated survivor participants would be valuable in better defining the multiprong T cell population and validate the findings.

If you’re interested in learning more on this topic, then check out some of our related content on emerging cell therapies and biology of T cells.

References

[1] Barry, M., Bleackley, R. Cytotoxic T lymphocytes: all roads lead to death. Nat Rev Immunol 2, 401–409 (2002). https://doi.org/10.1038/nri819.

[2] Zamora AE, Crawford JC, Thomas PG. Hitting the Target: How T Cells Detect and Eliminate Tumors. J Immunol. 2018 Jan 15;200(2):392-399. doi: 10.4049/jimmunol.1701413. PMID: 29311380; PMCID: PMC6116355.

[3] Dolton et al., 2023, Cell 186, 3333–3349 August 3, 2023 ª 2023 The Authors. Published by Elsevier Inc. https://doi.org/10.1016/j.cell.2023.06.020.

[4] Bilal Aslam and others, Proteomics: Technologies and Their Applications, Journal of Chromatographic Science, Volume 55, Issue 2, 1 February 2017, Pages 182–196, https://doi.org/10.1093/chromsci/bmw167.

[5] Kim SK, Cho SW. The Evasion Mechanisms of Cancer Immunity and Drug Intervention in the Tumor Microenvironment. Front Pharmacol. 2022 May 24;13:868695. doi: 10.3389/fphar.2022.868695.