Multimodal blood based proteomic profiling reveals insights into mechanisms of immunotherapy resistance

Many cancer patients treated with immune checkpoint blockade (ICB) do not have durable treatment responses. Circulating biomarkers have the potential to identify patients with primary resistance or early progression on therapy to alter treatment course and potentially avoid unnecessary toxicity. Unbiased multimodal proteomic profiling in blood has been underexplored due to the previously limited scalability of multiplexing technologies or cohorts lacking time-series sampling. To address this, we performed plasma proteomic profiling of >2900 proteins and high-dimensional mass cytometry of peripheral blood lymphocytes across serial time points in 250 metastatic melanoma patients on ICB treatment. We further obtained 92 patient-matched tumor samples, which were processed for single-cell and/or bulk RNA sequencing. Proteins upregulated post-ICB were associated with inflammatory pathways involving the activation of effector immune functions. Expression of genes corresponding to these proteins was higher in immune cells involved in recruitment and tumor reactivity. Expression of genes corresponding to plasma proteins more abundant in non-responders was highest in suppressive myeloid subsets and malignant cells. We further posit the involvement of these non-responder genes in immunosuppressive and pro-tumor interactions, which we confirm using publicly available spatial transcriptomic data. We also find that epithelial-specific proteins in the circulation of responders post-ICB associate with patient toxicity and likely originate from degradation of healthy tissues. Together, these data represent extensive potential peripheral biomarker characterization using paired blood and tumor samples in melanoma patients treated with ICB, and begin to elucidate the complex interplay between tumors and the systemic immune response within the host.

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Publication Details

Journal
Nature Communications
Published
2026-06-24
DOI
https://doi.org/10.1038/s41467-026-74790-7
Primary Topic
Advanced Biosensing Techniques and Applications
Type
article
Field-Weighted Citation Impact
0.00

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article

Multimodal blood based proteomic profiling reveals insights into mechanisms of immunotherapy resistance

Arnav Mehta, Marijana Ručević, Ryan J. Sullivan, Genevieve Marie Boland et al.
Nature Communications
Advanced Biosensing Techniques and Applications
article

Multimodal blood based proteomic profiling reveals insights into mechanisms of immunotherapy resistance

Arnav Mehta, Marijana Ručević, Ryan J. Sullivan, Genevieve Marie Boland, Long Cheng, Alexis M. Schneider, Emily M. Blaum, Keith T. Flaherty, Thomas J. LaSalle, Russell W. Jenkins, Milan Parikh, Sonia Cohen, Alexandra–Chloé Villani, Nir Hacohen, Deepika Yeramosu, Lynn Bi, Moshe Sade-Feldman, Michelle S. Kim, Steven M. Blum, Ryan Jin-hyung Park, Aleigha Lawless, William A. Michaud, Baolin Liu, Samuel J. Klempner, Tatyana Sharova, Jamey Guess, Amrita Kar, David Lieb, Gyulnara Kasumova, Elliot Woods, Samuel J. Wright, Izabella Zamora, Sarah Kang, Ngan Nguyen
article en

Abstract

Many cancer patients treated with immune checkpoint blockade (ICB) do not have durable treatment responses. Circulating biomarkers have the potential to identify patients with primary resistance or early progression on therapy to alter treatment course and potentially avoid unnecessary toxicity. Unbiased multimodal proteomic profiling in blood has been underexplored due to the previously limited scalability of multiplexing technologies or cohorts lacking time-series sampling. To address this, we performed plasma proteomic profiling of >2900 proteins and high-dimensional mass cytometry of peripheral blood lymphocytes across serial time points in 250 metastatic melanoma patients on ICB treatment. We further obtained 92 patient-matched tumor samples, which were processed for single-cell and/or bulk RNA sequencing. Proteins upregulated post-ICB were associated with inflammatory pathways involving the activation of effector immune functions. Expression of genes corresponding to these proteins was higher in immune cells involved in recruitment and tumor reactivity. Expression of genes corresponding to plasma proteins more abundant in non-responders was highest in suppressive myeloid subsets and malignant cells. We further posit the involvement of these non-responder genes in immunosuppressive and pro-tumor interactions, which we confirm using publicly available spatial transcriptomic data. We also find that epithelial-specific proteins in the circulation of responders post-ICB associate with patient toxicity and likely originate from degradation of healthy tissues. Together, these data represent extensive potential peripheral biomarker characterization using paired blood and tumor samples in melanoma patients treated with ICB, and begin to elucidate the complex interplay between tumors and the systemic immune response within the host.

Nature Communications
Broad Institute (US), The University of Texas MD Anderson Cancer Center (US), Harvard University (US), University of California, San Francisco (US), Massachusetts General Hospital (US), Olink (United States) (US), Global Cancer Institute (US), Center for Cancer Research (US), Massachusetts Institute of Technology (US), Biotronik (Switzerland) (CH)
Prostate Cancer Foundation, Massachusetts General Hospital, Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, Dana-Farber/Harvard Cancer Center, Massachusetts Life Sciences Center
Zero hunger
Openalex Percentile: Top 11%
Advanced Biosensing Techniques and Applications
DOIOpen Access PDFOpenAlex
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