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Early T Cell Infiltration Correlates with Anti-CTLA4 Treatment Response in Murine Cancer Models
Andrew A Almonte1, George Cavic1, Christina S E Carroll2
1Division of Biomedical Science and Biochemistry, Research School of Biology, The Australian National University, Canberra, Australia.
Abstract:
Immune checkpoint inhibitor (ICI) Abs are a revolutionary class of cancer treatment, but only ∼30% of patients receive a lasting benefit from therapy. Preclinical studies using animals from the same genetic backgrounds, challenged with the same cancer models, also show nonuniform responses. Most mouse studies that have evaluated tumor-infiltrating leukocytes after ICI therapy cannot directly correlate their findings with treatment outcomes, because terminal methods were used to acquire immune infiltrate data. In the present study, we used fine-needle aspiration (a nonterminal sampling method) to collect multiple aspirates over several days from s.c. implanted P815, CT26, and 4T1 mouse cancer models treated with ICI Abs. These aspirates were then analyzed with flow cytometry to directly correlate tumor-infiltrating leukocyte populations with treatment success. We found that the P815 and CT26 models respond well to anti-CTLA4 therapies. Among P815-challenged animals, mice that regressed following anti-CTLA4 treatment showed significant increases in CD8+ T cells on days 3, 5, and 7 and in CD4+ T cells on days 5 and 7 and a decrease in macrophages and monocytes on days 3, 5, and 7 after treatment. Similar results were obtained in the CT26 model on day 11 posttreatment. Our study is the first, to our knowledge, to directly correlate early tumor infiltration of T cells with anti-CTLA4 treatment success, thus providing a mechanistic clue toward understanding why alloidentical mice challenged with identical tumors do not respond uniformly to ICI therapies.
Insights
Immune checkpoint inhibitor (ICI) antibody therapy benefits vary. This study links early T cell infiltration in tumors to successful anti-CTLA4 treatment in mouse models, offering insights into treatment response variability.
Area of Science:
- Immunology
- Cancer Biology
- Translational Oncology
Background:
- Immune checkpoint inhibitor (ICI) antibodies offer revolutionary cancer treatment, yet only ~30% of patients achieve lasting benefits.
- Nonuniform responses to ICI therapy are observed even in preclinical models, with limited ability to correlate immune infiltrate data with outcomes due to terminal sampling methods.
- Understanding the early immune dynamics correlating with treatment success is crucial for improving ICI efficacy.
Purpose of the Study:
- To investigate the direct correlation between early tumor-infiltrating leukocyte populations and treatment success in mouse cancer models treated with ICI antibodies.
- To establish a nonterminal method for longitudinal monitoring of immune infiltrates during ICI therapy.
- To provide mechanistic insights into the variable responses observed in ICI therapy.
Main Methods:
- Utilized fine-needle aspiration, a nonterminal sampling technique, to collect serial aspirates from P815, CT26, and 4T1 subcutaneous mouse cancer models treated with ICI antibodies.
- Analyzed immune infiltrates using flow cytometry to quantify leukocyte populations.
- Directly correlated changes in immune cell populations with treatment outcomes (tumor regression).
Main Results:
- P815 and CT26 mouse cancer models demonstrated positive responses to anti-CTLA4 therapies.
- In P815 models, successful anti-CTLA4 treatment correlated with significant increases in CD8+ T cells (days 3, 5, 7) and CD4+ T cells (days 5, 7), alongside decreased macrophages and monocytes (days 3, 5, 7).
- Similar immune infiltration patterns were observed in the CT26 model, correlating with treatment success.
Conclusions:
- This study is the first to directly correlate early tumor infiltration of T cells with anti-CTLA4 treatment success in preclinical models.
- The findings provide a mechanistic clue for understanding the non-uniform responses to ICI therapies.
- Longitudinal monitoring of immune infiltrates via nonterminal sampling can offer valuable insights into treatment efficacy.
