This week we profile a recent publication in PNAS from the laboratory of Dr. Evan Newell (pictured, third from right)
with first author Dr. Shamin Li (pictured, second from right) at Fred Hutch.
Can you provide a brief overview of your lab’s current research focus?
The lab focuses on analyzing cellular immune responses in the context of cancer and infectious disease. Although we mostly perform human studies, we also use mice for some of our studies such as this one. Our long-term goal is to identify novel biomarkers or therapeutic strategies based on the characteristics of disease-relevant immune cells. In addition to unbiased cellular analysis approaches, we focus particularly on antigen-specific cells where we can be more confident that these cells are actively involved in the disease. To identify and profile antigen-specific T (and sometimes B cells), we use various high dimensional cellular analysis methods such as mass cytometry, single-cell sequencing-based methods, and we are starting to use some spatial transcriptomic/proteomic methods. In this study, we relied most heavily on mass cytometry, which is a form of flow cytometry based on atomic mass spectrometry that uses heavy metal tags on antibodies instead of fluorophores. We were early adopters of this technology and have used it for many years as the basis for our analyses of antigen-specific T cell responses in various disease contexts.
What is the significance of the findings in this publication?
Even though immune checkpoint blockade (ICB) therapies (e.g. PD-1, CTLA-4) have completely revolutionized the oncology field, we need at present to better understand the mechanisms behind the uneven response and to improve the efficacy of these treatments. Following the group’s interest in antigen-specific T cells, we characterized tumor-specific T cells in an ICB-resistant mouse tumor model, Lewis Lung Carcinoma (LLC).
Using a high throughput screening method based on mass cytometry, we predicted and identified ex vivo an immunodominant tumor mutation-derived neoantigen (mRiok1) recognized by tumor-infiltrating CD8 T cells. Upon ICB monotherapy (targeting anti-PD1 or anti-CTLA4) and neoantigen vaccination, these cells massively expand but remain exhausted and dysfunctional as in non-treated conditions. Combined therapy leads to slower tumor growth as we detect more neoantigen-specific cells expressing a progenitor-like phenotype and producing pro-inflammatory cytokines, yet it does not induce tumor regression.
This study indicates that neoantigen-specific T cells alone could be not sufficient in leading successful anti-tumor responses (especially in cold epithelial tumors). We anticipate that this will open avenues in reexamining the role of tumor-specific T cells in cancer immunotherapy and in developing new therapeutic strategies.
What are the next steps for this research?
As we provide a straightforward and accessible model to study mouse tumor neoantigens, we hope that this work will facilitate future research investigating resistance mechanisms in immunotherapy non-responder tumors. Several paths could be explored as follow-up studies, which could either focus on expanding functional tumor-specific T cells or on understanding the impact of the TME to improve treatment efficacy.
If you’d like us to mention your funding sources, please list them.
For this work, we were funded by new-development funding from the Fred Hutchinson Cancer Research Center. We were also funded by The Andy Hill Endowment Distinguished Researcher Program which is part of the Andy Hill CARE Fund from the State of Washington. The group photo I’m providing is from a CARE Fund event that we attended at the Governor’s Mansion in Olympia.
