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Published on: February 8, 2018
Dissecting response to neoadjuvant immunotherapy-treated melanoma using cancer-immunity cycle-associated signatures
S C M A Wijnen1, P Dimitriadis1, I L M Reijers1
1Department of Medical Oncology, Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
Abstract:
Neoadjuvant combination therapy with anti-PD-1 and anti-CTLA4 agents has significantly improved long-term survival in patients with metastatic melanoma, yet not all patients respond to treatment. Responders often exhibit upregulated baseline inflammatory signatures; however, these markers capture only a single facet of the Cancer-Immunity Cycle-a comprehensive model describing the sequential steps required for effective anti-cancer immunity. To determine whether non-responsiveness to immunotherapy arises from single or multiple 'defective' steps, we analyzed in melanoma patients, treated with neoadjuvant immunotherapy, gene signatures representing each step of the cycle. Patients not achieving a major pathological response showed overall lower expression of these signatures. Among the 'immune-hot' patients, we identified a low response subgroup defective in one step ('homing-to-the-tumor,' involving CXCL9 and CXCL10), making this a promising target for improving their outcomes.
Insights
Immunotherapy improves survival in metastatic melanoma, but not all patients benefit. This study found that some non-responders have defects in the
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Neoadjuvant anti-PD-1 and anti-CTLA4 combination therapy offers improved survival for metastatic melanoma patients.
- However, not all patients achieve a major pathological response to this immunotherapy.
- Baseline inflammatory signatures in responders are known, but a comprehensive understanding of non-response is lacking.
Purpose of the Study:
- To investigate whether non-responsiveness to neoadjuvant immunotherapy in melanoma is due to single or multiple defects in the Cancer-Immunity Cycle.
- To identify specific steps within the Cancer-Immunity Cycle that are compromised in non-responding patients.
Main Methods:
- Analysis of gene signatures representing each step of the Cancer-Immunity Cycle in melanoma patients undergoing neoadjuvant immunotherapy.
- Comparison of gene expression profiles between patients who achieved a major pathological response and those who did not.
- Stratification of 'immune-hot' patients to identify subgroups with specific molecular defects.
Main Results:
- Patients not achieving a major pathological response generally exhibited lower expression of Cancer-Immunity Cycle gene signatures.
- Within the 'immune-hot' patient subgroup, a subset of low responders was identified.
- This low response subgroup demonstrated a specific defect in the 'homing-to-the-tumor' step, characterized by low expression of CXCL9 and CXCL10.
Conclusions:
- Non-responsiveness to neoadjuvant immunotherapy in melanoma may stem from specific defects in the Cancer-Immunity Cycle.
- Targeting the 'homing-to-the-tumor' step, particularly by modulating CXCL9 and CXCL10, presents a potential strategy to improve outcomes for non-responding melanoma patients.
- Understanding these specific immune cycle defects can guide the development of more effective combination immunotherapies.
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