Why the Outcome of Anti‐Tumor Immune Responses is Heterogeneous: A Novel Idea in the Context of Immunological Heterogeneity in Cancers

Wang, Jing H.

doi:10.1002/bies.202000024

Cited by 10 publications

(9 citation statements)

References 68 publications

(82 reference statements)

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“…These data suggest that the presence of a single tumor-reactive TCR clonotype is insufficient to mediate therapeutic effects of anti-PD-L1, and a combination of multiple clonotypes may be needed for efficacy. We further hypothesize that different recipients harbor intrinsic differences in their TCR repertoires that likely affect the chance of mounting an effective ICI response ( 1 ). For instance, differences in TCR repertoire could alter the frequency of tumor-reactive clones or the optimal composition of such clones mediating ICI responses.…”

Section: Discussionmentioning

confidence: 99%

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Divergent outcomes of anti-PD-L1 treatment coupled with host-intrinsic differences in TCR repertoire and distinct T cell activation states in responding versus non-responding tumors

John

Woolaver²,

Popolizio³

et al. 2022

Front. Immunol.

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Differential responses to immune checkpoint inhibitors (ICI) may be attributed to tumor-intrinsic factors or environmental cues; however, these mechanisms cannot fully explain the variable ICI responses in different individuals. Here, we investigate the potential contribution of immunological heterogeneity with a focus on differences in T-cell receptor (TCR) repertoire to ICI responses, which has not been defined previously. To reveal additional factors underlying heterogeneous responses to ICI, we employed a squamous cell carcinoma (SCC) mouse model in which tumor-bearing recipients unambiguously diverged into responders (R) or non-responders (NR) upon anti-PD-L1 treatment. Treatment efficacy absolutely required CD8 T-cells and correlated positively with effector functions of CD8 tumor-infiltrating lymphocytes (TILs). We showed that TCR repertoires exhibited a similar magnitude of clonal expansion in R vs. NR CD8 TILs. However, the top expanded TCR clonotypes appeared to be mutually exclusive between R and NR CD8 TILs, which also occurred in a recipient-specific manner, demonstrating preferential expansion of distinct TCR clonotypes against the same SCC tumor. Unexpectedly, R vs. NR CD8 TILs reached all activation clusters and did not exhibit substantial global differences in transcriptomes. By linking single-cell transcriptomic data with unique TCR clonotypes, CD8 TILs harboring top TCR clonotypes were found to occupy distinct activation clusters and upregulate genes favoring anti-tumor immunity to different extents in R vs. NR. We conclude that stochastic differences in CD8 TIL TCR repertoire and distinct activation states of top TCR clonotypes may contribute to differential anti-PD-L1 responses. Our study suggests that host-intrinsic immunological heterogeneity may offer a new explanation for differential ICI responses in different individuals, which could impact on strategies for personalized cancer immunotherapy.

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Section: Discussionmentioning

confidence: 99%

“…A fundamental question in cancer immunology is why the outcome of anti-tumor immune responses is so heterogeneous and highly variable in different individuals ( 1 ). For instance, it is well-known that some cancer patients responded to immune checkpoint inhibitors (ICI), while others were completely unresponsive ( 2 , 3 ).…”

Section: Introductionmentioning

confidence: 99%

Divergent outcomes of anti-PD-L1 treatment coupled with host-intrinsic differences in TCR repertoire and distinct T cell activation states in responding versus non-responding tumors

John

Woolaver²,

Popolizio³

et al. 2022

Front. Immunol.

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“…Third, we speculate that different recipients harbor intrinsic differences in their TCR repertoire that may influence the chance of a successful antitumor immune response. 61 For instance, such differences in TCR repertoire may affect the frequency of neoAg-reactive clones or the optimal composition of such clones that tips the balance between tumor eradication and outgrowth. We suggest that the A223 model might be immensely useful for studying heterogeneity, due to its unique and inherent ability to elicit heterogeneous antitumor immune responses (eg, spontaneous tumor eradication vs outgrowth), and its potential to harbor multiple poorly-immunogenic neoAgs.…”

Section: Discussionmentioning

confidence: 99%

Differences in TCR repertoire and T cell activation underlie the divergent outcomes of antitumor immune responses in tumor-eradicating versus tumor-progressing hosts

Woolaver

Wang

Krinsky

et al. 2021

J Immunother Cancer

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BackgroundAntitumor immunity is highly heterogeneous between individuals; however, underlying mechanisms remain elusive, despite their potential to improve personalized cancer immunotherapy. Head and neck squamous cell carcinomas (HNSCCs) vary significantly in immune infiltration and therapeutic responses between patients, demanding a mouse model with appropriate heterogeneity to investigate mechanistic differences.MethodsWe developed a unique HNSCC mouse model to investigate underlying mechanisms of heterogeneous antitumor immunity. This model system may provide a better control for tumor-intrinsic and host-genetic variables, thereby uncovering the contribution of the adaptive immunity to tumor eradication. We employed single-cell T-cell receptor (TCR) sequencing coupled with single-cell RNA sequencing to identify the difference in TCR repertoire of CD8 tumor-infiltrating lymphocytes (TILs) and the unique activation states linked with different TCR clonotypes.ResultsWe discovered that genetically identical wild-type recipient mice responded heterogeneously to the same squamous cell carcinoma tumors orthotopically transplanted into the buccal mucosa. While tumors initially grew in 100% of recipients and most developed aggressive tumors, ~25% of recipients reproducibly eradicated tumors without intervention. Heterogeneous antitumor responses were dependent on CD8 T cells. Consistently, CD8 TILs in regressing tumors were significantly increased and more activated. Single-cell TCR-sequencing revealed that CD8 TILs from both growing and regressing tumors displayed evidence of clonal expansion compared with splenic controls. However, top TCR clonotypes and TCR specificity groups appear to be mutually exclusive between regressing and growing TILs. Furthermore, many TCRα/TCRβ sequences only occur in one recipient. By coupling single-cell transcriptomic analysis with unique TCR clonotypes, we found that top TCR clonotypes clustered in distinct activation states in regressing versus growing TILs. Intriguingly, the few TCR clonotypes shared between regressors and progressors differed greatly in their activation states, suggesting a more dominant influence from tumor microenvironment than TCR itself on T cell activation status.ConclusionsWe reveal that intrinsic differences in the TCR repertoire of TILs and their different transcriptional trajectories may underlie the heterogeneous antitumor immune responses in different hosts. We suggest that antitumor immune responses are highly individualized and different hosts employ different TCR specificities against the same tumors, which may have important implications for developing personalized cancer immunotherapy.

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“…Additionally, the presence of responders and nonresponders highlights the importance of personalized immunotherapy; although all the mouse recipients were genetically identical, there were two distinct outcomes of mice treated with bintrafusp alfa. This may be due to clonal differences in tumor-initiating cells, or it may be caused by host T cell clonotype variation between mice 50 . Although responders had fewer tumor cells than nonresponders, the reduction was evenly spread across all UMAP clusters that made up the “tumor cells” and “dividing tumor cells” categories; this suggests that tumor cell heterogeneity alone is not an indicator of responders to bintrafusp alfa therapy.…”

Section: Discussionmentioning

confidence: 99%

Distinct immune microenvironment profiles of therapeutic responders emerge in combined TGFβ/PD-L1 blockade-treated squamous cell carcinoma

et al. 2021

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Transforming growth factor beta (TGFβ) and programmed death-ligand 1 (PD-L1) are often overproduced in refractory squamous cell carcinoma (SCC). We examined spatial patterns of PD-L1+ cells in mouse and human SCCs and found that PD-L1 was primarily expressed on infiltrating leukocytes. Although combined TGFβ and PD-L1 blockade are undergoing cancer clinical trials, there are no predictive markers for therapeutic responders. To address this, we used both a small molecule TGFβ inhibitor in combination with anti-PD-L1 and a bifunctional fusion protein targeting both TGFβ and PD-L1 to treat mouse SCCs and found TGFβ inhibition enhanced PD-L1 blockade-induced tumor eradication in multiple tumor models. Furthermore, we identified distinct cell populations of responders and non-responders to bintrafusp alfa, with responders showing a shift toward a more immune-permissive microenvironment. The cellular and molecular signatures of responders versus non-responders to combined TGFβ and PD-L1 blockade provide important insights into future personalized immunotherapy in SCC.

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Why the Outcome of Anti‐Tumor Immune Responses is Heterogeneous: A Novel Idea in the Context of Immunological Heterogeneity in Cancers

Cited by 10 publications

References 68 publications

Divergent outcomes of anti-PD-L1 treatment coupled with host-intrinsic differences in TCR repertoire and distinct T cell activation states in responding versus non-responding tumors

Divergent outcomes of anti-PD-L1 treatment coupled with host-intrinsic differences in TCR repertoire and distinct T cell activation states in responding versus non-responding tumors

Differences in TCR repertoire and T cell activation underlie the divergent outcomes of antitumor immune responses in tumor-eradicating versus tumor-progressing hosts

Distinct immune microenvironment profiles of therapeutic responders emerge in combined TGFβ/PD-L1 blockade-treated squamous cell carcinoma

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