A study published in Nature Communications investigates the molecular patterns of resistance to immune checkpoint blockade (ICB) in melanoma. The research analyzed biopsies from 44 melanoma patients who had progressed on anti-CTLA4 or anti-PD1 monotherapy. The findings reveal that approximately 25% of ICB-resistant cases have genetic alterations in antigen presentation and interferon gamma signaling pathways. Anti-CTLA4 resistant lesions show sustained immune responses, while anti-PD1 resistant tumors are generally immune poor with non-expanded TCR clones. These tumors also have reduced fractions of PD1+ CD8+ T cells compared to ICB-naive metastases. The study highlights differences between anti-CTLA4 and anti-PD1 resistance, which may explain varying clinical outcomes of therapy sequences and combinations. The research also shows that immune checkpoint blockade therapy has had significant clinical success in advanced melanoma, with objective response rates of 19%, 45%, and 58% for anti-CTLA4, anti-PD1, and combination therapy, respectively. Despite this progress, a large fraction of patients do not benefit from ICB. The majority of non-responders are primary resistant, while a smaller fraction acquire resistance during treatment. The study found that genetic alterations in antigen presentation and interferon gamma signaling pathways are associated with ICB resistance. Additionally, the study found that immune regulatory pathways differ between anti-CTLA4 and anti-PD1 resistant melanomas. The research also identified distinct tumor cell states in melanoma metastases, with anti-PD1 resistant tumors showing a de-differentiated phenotype lacking MHC-I expression. The study concludes that ICB resistance is complex and involves different molecular mechanisms for anti-CTLA4 and anti-PD1 resistance. The findings highlight the need for further understanding of the molecular mechanisms underlying ICB resistance in melanoma.A study published in Nature Communications investigates the molecular patterns of resistance to immune checkpoint blockade (ICB) in melanoma. The research analyzed biopsies from 44 melanoma patients who had progressed on anti-CTLA4 or anti-PD1 monotherapy. The findings reveal that approximately 25% of ICB-resistant cases have genetic alterations in antigen presentation and interferon gamma signaling pathways. Anti-CTLA4 resistant lesions show sustained immune responses, while anti-PD1 resistant tumors are generally immune poor with non-expanded TCR clones. These tumors also have reduced fractions of PD1+ CD8+ T cells compared to ICB-naive metastases. The study highlights differences between anti-CTLA4 and anti-PD1 resistance, which may explain varying clinical outcomes of therapy sequences and combinations. The research also shows that immune checkpoint blockade therapy has had significant clinical success in advanced melanoma, with objective response rates of 19%, 45%, and 58% for anti-CTLA4, anti-PD1, and combination therapy, respectively. Despite this progress, a large fraction of patients do not benefit from ICB. The majority of non-responders are primary resistant, while a smaller fraction acquire resistance during treatment. The study found that genetic alterations in antigen presentation and interferon gamma signaling pathways are associated with ICB resistance. Additionally, the study found that immune regulatory pathways differ between anti-CTLA4 and anti-PD1 resistant melanomas. The research also identified distinct tumor cell states in melanoma metastases, with anti-PD1 resistant tumors showing a de-differentiated phenotype lacking MHC-I expression. The study concludes that ICB resistance is complex and involves different molecular mechanisms for anti-CTLA4 and anti-PD1 resistance. The findings highlight the need for further understanding of the molecular mechanisms underlying ICB resistance in melanoma.