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Updated: Jun 5, 2025
Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
Published on: February 8, 2018
TIGIT and PD-L1 co-blockade promotes clonal expansion of multipotent, non-exhausted antitumor T cells by facilitating
Katherine Nutsch1, Karl L Banta1, Thomas D Wu1
1Genentech, South San Francisco, CA, USA.
Abstract:
Blockade of immune checkpoints PD-1 and TIGIT has demonstrated activity in mouse tumor models and human patients with cancer. Although these coinhibitory receptors can restrict signaling in CD8+ T cells by regulating their associated co-stimulatory receptors CD28 and CD226, the functional consequences of combining PD-1 and TIGIT blockade remain poorly characterized. In mouse tumor models, we show that combination blockade elicited CD226-driven clonal expansion of tumor antigen-specific CD8+ T cells. The expanded clones emerged from a population of stem-like cells in draining lymph nodes, entering the blood as a previously unidentified single-phenotype, multiclonal population. Upon reaching the tumor, these transiting cells expanded further and differentiated into effector or exhausted T cells, with combination blockade restricting entry into the exhaustion pathway by favoring co-stimulation. Thus, PD-1 and TIGIT inhibition helps shape the repertoire of tumor-reactive CD8+ T cells in draining lymph nodes and determines their immunological fate in the tumor to enhance therapeutic benefit. Analysis of clinical trial samples suggests a similar mechanism may also occur in patients with cancer.
Insights
Combining PD-1 and TIGIT blockade promotes CD8+ T cell expansion and differentiation, enhancing anti-tumor immunity. This approach shapes T cell responses in lymph nodes and tumors, potentially improving cancer therapy.
Area of Science:
- Immunology
- Cancer Biology
- T cell Biology
Background:
- Immune checkpoint inhibitors PD-1 and TIGIT are used in cancer therapy.
- Their combined blockade effects on CD8+ T cells are not fully understood.
- These checkpoints regulate T cell signaling via CD28 and CD226.
Purpose of the Study:
- To investigate the functional consequences of combined PD-1 and TIGIT blockade.
- To elucidate the mechanism of CD8+ T cell expansion and differentiation under combination blockade.
- To determine the impact on anti-tumor immunity.
Main Methods:
- Utilized mouse tumor models.
- Analyzed CD8+ T cell populations in draining lymph nodes and tumors.
- Examined T cell phenotypes, clonal expansion, and differentiation pathways.
- Analyzed clinical trial samples.
Main Results:
- Combination blockade induced CD226-dependent clonal expansion of tumor-specific CD8+ T cells.
- Expanded T cells originated from stem-like cells in lymph nodes.
- These cells formed a unique circulating population before tumor infiltration.
- Combination blockade promoted T cell differentiation into effector cells over exhaustion by favoring co-stimulation.
- Similar mechanisms were suggested in human cancer patients.
Conclusions:
- Combined PD-1 and TIGIT blockade shapes the CD8+ T cell repertoire in draining lymph nodes.
- It influences the immunological fate of T cells within tumors, enhancing therapeutic benefit.
- This dual blockade strategy represents a promising approach for cancer immunotherapy.
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