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Conserved immuno-collagenic subtypes predict response to immune checkpoint blockade
Jie Mei1,2, Yun Cai3, Rui Xu1,2
1Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P. R. China.
Background:
Immune checkpoint blockade (ICB) has revolutionized the treatment of various cancer types. Despite significant preclinical advancements in understanding mechanisms, identifying the molecular basis and predictive biomarkers for clinical ICB responses remains challenging. Recent evidence, both preclinical and clinical, underscores the pivotal role of the extracellular matrix (ECM) in modulating immune cell infiltration and behaviors. This study aimed to create an innovative classifier that leverages ECM characteristics to enhance the effectiveness of ICB therapy.
Methods:
We analyzed transcriptomic collagen activity and immune signatures in 649 patients with cancer undergoing ICB therapy. This analysis led to the identification of three distinct immuno-collagenic subtypes predictive of ICB responses. We validated these subtypes using the transcriptome data from 9,363 cancer patients from The Cancer Genome Atlas (TCGA) dataset and 1,084 in-house samples. Additionally, novel therapeutic targets were identified based on these established immuno-collagenic subtypes.
Results:
Our categorization divided tumors into three subtypes: "soft & hot" (low collagen activity and high immune infiltration), "armored & cold" (high collagen activity and low immune infiltration), and "quiescent" (low collagen activity and immune infiltration). Notably, "soft & hot" tumors exhibited the most robust response to ICB therapy across various cancer types. Mechanistically, inhibiting collagen augmented the response to ICB in preclinical models. Furthermore, these subtypes demonstrated associations with immune activity and prognostic predictive potential across multiple cancer types. Additionally, an unbiased approach identified B7 homolog 3 (B7-H3), an available drug target, as strongly expressed in "armored & cold" tumors, relating with poor prognosis.
Conclusion:
This study introduces histopathology-based universal immuno-collagenic subtypes capable of predicting ICB responses across diverse cancer types. These findings offer insights that could contribute to tailoring personalized immunotherapeutic strategies for patients with cancer.
Insights
This study identifies three tumor subtypes based on extracellular matrix (ECM) and immune cell activity, predicting response to immune checkpoint blockade (ICB) therapy. "Soft & hot" tumors show the best ICB response, offering new strategies for cancer treatment.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Immune checkpoint blockade (ICB) has transformed cancer therapy, but predicting patient response remains a challenge.
- The extracellular matrix (ECM) plays a critical role in modulating immune cell infiltration and anti-tumor immunity.
- Understanding the interplay between ECM and immune microenvironment is crucial for improving ICB efficacy.
Purpose of the Study:
- To develop an innovative classifier leveraging ECM characteristics to predict ICB therapy response.
- To identify novel therapeutic targets based on distinct immuno-collagenic subtypes.
- To enhance the effectiveness of ICB by stratifying patients based on tumor microenvironment features.
Main Methods:
- Transcriptomic collagen activity and immune signatures were analyzed in 649 patients undergoing ICB therapy.
- Three distinct immuno-collagenic subtypes were identified and validated using TCGA and in-house datasets (9,363 and 1,084 samples, respectively).
- Preclinical models were used to investigate the mechanistic role of collagen in ICB response.
Main Results:
- Three subtypes were defined: "soft & hot" (low collagen, high immune), "armored & cold" (high collagen, low immune), and "quiescent" (low collagen, low immune).
- "Soft & hot" tumors demonstrated the most robust response to ICB across cancer types; collagen inhibition enhanced ICB efficacy in preclinical models.
- B7-H3 was identified as a potential therapeutic target, highly expressed in "armored & cold" tumors associated with poor prognosis.
Conclusions:
- Universal immuno-collagenic subtypes, identifiable via histopathology, can predict ICB responses across diverse cancers.
- These subtypes provide insights for tailoring personalized immunotherapeutic strategies.
- Targeting ECM-immune interactions and specific biomarkers like B7-H3 may improve ICB outcomes.
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