Prior anti-CTLA-4 therapy impacts molecular characteristics associated with anti-PD-1 response in advanced melanoma
Katie M Campbell1, Meelad Amouzgar2, Shannon M Pfeiffer3
1Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Abstract:
Immune checkpoint inhibitors (ICIs), including CTLA-4- and PD-1-blocking antibodies, can have profound effects on tumor immune cell infiltration that have not been consistent in biopsy series reported to date. Here, we analyze seven molecular datasets of samples from patients with advanced melanoma (N = 514) treated with ICI agents to investigate clinical, genomic, and transcriptomic features of anti-PD-1 response in cutaneous melanoma. We find that prior anti-CTLA-4 therapy is associated with differences in genomic, individual gene, and gene signatures in anti-PD-1 responders. Anti-CTLA-4-experienced melanoma tumors that respond to PD-1 blockade exhibit increased tumor mutational burden, inflammatory signatures, and altered cell cycle processes compared with anti-CTLA-4-naive tumors or anti-CTLA-4-experienced, anti-PD-1-nonresponsive melanoma tumors. We report a harmonized, aggregate resource and suggest that prior CTLA-4 blockade therapy is associated with marked differences in the tumor microenvironment that impact the predictive features of PD-1 blockade therapy response.
Insights
Prior anti-CTLA-4 therapy significantly alters tumor microenvironment and predictive features for anti-PD-1 response in advanced melanoma patients. This impacts how we predict treatment success.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Immune checkpoint inhibitors (ICIs) like CTLA-4 and PD-1 antibodies show variable effects on tumor immune infiltration.
- Understanding factors influencing anti-PD-1 response in melanoma is crucial for effective treatment.
Purpose of the Study:
- To investigate clinical, genomic, and transcriptomic features associated with anti-PD-1 response in advanced cutaneous melanoma.
- To analyze the impact of prior anti-CTLA-4 therapy on anti-PD-1 treatment outcomes.
Main Methods:
- Analysis of seven molecular datasets from 514 advanced melanoma patients treated with ICIs.
- Comparison of genomic, individual gene, and gene signatures between responders and non-responders.
Main Results:
- Prior anti-CTLA-4 therapy is linked to distinct genomic and transcriptomic profiles in anti-PD-1 responders.
- Melanoma tumors responding to PD-1 blockade after CTLA-4 treatment show increased tumor mutational burden and inflammatory signatures.
- Altered cell cycle processes were observed in responsive, previously CTLA-4 treated tumors.
Conclusions:
- Prior CTLA-4 blockade therapy significantly modifies the tumor microenvironment.
- These modifications impact the predictive features for response to subsequent PD-1 blockade therapy.
- A harmonized resource is provided to aid further research into ICI treatment response.
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