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Published on: June 12, 2021
Tumor-Associated Antigen Burden Correlates with Immune Checkpoint Blockade Benefit in Tumors with Low Levels of
Yue Wang1,2, Mengying Hu1,2, Olivera J Finn1,3
1UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
Abstract:
Tumor-associated antigens (TAA) are important targets for cancer vaccines. However, TAA-based vaccines have not yet achieved their full potential in clinical trials. In contrast, immune checkpoint blockade (ICB) has emerged as an effective therapy, leading to durable responses in selected patients with cancer. To date, few generalizable associations between TAAs and ICB benefit have been reported, with most studies focusing on melanoma, which has the highest mutation rate in cancer. In this study, we developed a TAA burden (TAB) algorithm based on known and putative TAAs and investigated the association of TAB with ICB benefit. Analysis of the IMvigor210 patient cohort of urothelial carcinoma treated with anti-PDL1 revealed that high tumor mutation burden weakened the association of TAB with ICB benefit. Furthermore, TAB correlated with ICB efficacy in tumors characterized by negative PDL1 staining on immune cells; however, high levels of PDL1 staining on immune cells were linked to T-cell exhaustion. Validation across independent clinical datasets-including urothelial carcinoma cohorts treated with anti-PD1/PDL1 agents and neoadjuvant anti-PD1 trials for head and neck cancers-corroborated the finding that TAB correlates with ICB benefit in tumors with low T-cell exhaustion. Pan-cancer analyses revealed that in most cancer entities, tumors with higher T-cell exhaustion exhibited lower TAB levels, implying possible immunoediting of TAAs in tumors with established antitumor immunity. Our study challenges the prevailing notion of a lack of association between TAAs and ICB response. It also underscores the need for future investigations into the immunogenicity of TAAs and TAA-based vaccine strategies in tumors with low levels of T-cell exhaustion.
Insights
Tumor-associated antigen (TAA) burden correlates with immune checkpoint blockade (ICB) benefit, especially in cancers with low T-cell exhaustion. This finding challenges current notions and suggests new vaccine strategies.
Area of Science:
- Immunology
- Oncology
- Cancer Vaccines
Background:
- Tumor-associated antigens (TAAs) are key targets for cancer vaccines, but their clinical success has been limited.
- Immune checkpoint blockade (ICB) is an effective cancer therapy, yet associations between TAAs and ICB benefit are not well-established.
- Most research has focused on melanoma, limiting generalizability to other cancer types.
Purpose of the Study:
- To develop a TAA burden (TAB) algorithm to assess the association between TAAs and ICB efficacy.
- To investigate how tumor mutation burden and PD-L1 expression influence the TAB-ICB benefit relationship.
- To explore the role of T-cell exhaustion in the context of TAB and ICB response across various cancers.
Main Methods:
- Developed a TAA burden (TAB) algorithm using known and putative TAAs.
- Analyzed the IMvigor210 cohort (urothelial carcinoma treated with anti-PDL1) and independent datasets (urothelial carcinoma, head and neck cancers).
- Correlated TAB with ICB efficacy, considering tumor mutation burden, PD-L1 staining, and T-cell exhaustion markers.
Main Results:
- High tumor mutation burden weakened the association between TAB and ICB benefit.
- TAB correlated with ICB efficacy in tumors with low PD-L1 expression on immune cells.
- TAB positively correlated with ICB benefit in tumors exhibiting low T-cell exhaustion, observed across multiple cancer types.
- Tumors with high T-cell exhaustion generally showed lower TAB levels, suggesting immunoediting.
Conclusions:
- The study establishes a link between TAA burden and ICB response, particularly in tumors with low T-cell exhaustion.
- Findings challenge the notion that TAAs are not associated with ICB efficacy.
- Highlights the need for further research into TAA immunogenicity and vaccine strategies for tumors with low T-cell exhaustion.
