The DNA damage response (DDR) is a collective term for the plethora of different intra- and intercellular signaling events and enzyme activities that result from the induction and detection of DNA damage (1). As a hot direction, there are many pieces of research related to DDR at present, which shows that DDR not only can predict the risk of breast cancer, ovarian cancer, and other cancers but also is related to the efficacy of various treatments, such as the presence of BRCA [a member of the homologous recombination repair (HRR) pathway] mutation that has been reported to correlate with the risk of breast cancer and the efficacy of PARP inhibitors, and the reports that multiple DDR pathway genes, including BRCA, predict the efficacy of immunotherapy for advanced urothelial carcinoma (2–4). According to previous literature, the DDR system comprises eight pathways, namely, mismatch repair (MMR), base excision repair (BER), checkpoint factors, Fanconi anemia (FA), HRR, nucleotide excision repair (NER), non-homologous end-joining (NEJ), and DNA translesion synthesis (TLS) (5). The current results show that the role of each pathway is different. For example, mutations in MLH1, MSH2, MSH6, or PMS2 in the MMR pathway can predict the immunotherapy benefit of patients with colorectal cancer (6), and PRO found and the TBCRC 048 study demonstrated, respectively, that Olaparib (PARP inhibitor) has a favorable benefit in prostate and breast cancer patients with HRR gene mutations (7, 8). PALB2, an important member of the HRR pathway, is frequently observed in cancer. In lung cancer, PALB2 mutations occurred at 1.8% of cases, which is the highest rate among all cancer types (9). PALB2 has been explored in the field of chemotherapy, and the presence of PALB2 mutation has been reported to be correlated with improved clinical outcomes in non-small cell lung cancer (NSCLC) treated with platinum-based chemotherapy (10). None of the previously reported studies of the correlation between the DDR gene and lung cancer immunotherapy has independently verified PALB2 (11–13). Therefore, it is necessary to analyze the PALB2 mutation characteristics in the Chinese NSCLC population and demonstrate whether PALB2 mutation is associated with immunotherapy responses. In this study, we attempted to analyze the characteristics and correlation with the immunotherapy biomarker of PALB2 mutation among advanced Chinese NSCLC patients. Furthermore, the relationship between PALB2 and response to immunotherapy was analyzed in a public cohort.

The results showed that neither PALB2^smut nor PALB2^gmut was associated with these immunotherapy biomarkers, except that PALB2^smut was associated with significantly higher TMB. PALB2 mutations are not associated with the prognosis of immunotherapy in NSCLC patients.

Since the 2017 V3 version of the NCCN breast cancer guidelines for the first time added the PARP inhibitor olaparib as a treatment option for patients with HER-2 negative BRCA1/2 (members of the HRR pathway) mutations (16), the significance of the DDR gene (including the HRR gene) in the guidance of therapy has attracted more and more attention, including multiple directions of chemotherapy, targeted therapy, and immunotherapy. Similarly, the prognostic impact of HRR gene on NSCLC treatment has also been confirmed; for example, a study published in Cancer Res in 2018 found a correlation between DDR pathway genes and immunotherapy efficacy, but mostly focus on co-mutations from two kinds of mutations of DDR pathway, and do not discuss individual genes (11). Similarly, a study of 266 NSCLC patients receiving immunotherapy published in Clin Cancer Res in 2020 showed that patients with mutations in any of DDR genes had significantly better prognosis than those without DDR mutations. Notably, the genes of the HRR pathway were also included in this study, but there are only two patients that harbored PALB2 (member of the HRR pathway) gene mutation, so the impact of PALB2 mutation on the prognosis of NSCLC patients was not analyzed. As the number of patients carrying each gene variation in the above study varied greatly and each subset was not analyzed, the level of evidence obtained was not high, which was also mentioned in the Discussion section (12). Therefore, this is not inconsistent with the conclusion in this study that PALB2 mutation is not associated with immunotherapy prognosis. In fact, the results of the recently published Imagyn050 study showed that ovarian cancer patients with BRCA1/2 gene mutations were insensitive to immunotherapy, suggesting that not all DDR or HRR genes can be considered prognostic factors for immunotherapy (17). Moreover, for the relationship between PALB^smut and TMB, PALB^smut may be an epiphenomenon of a high TMB, rather than causing themselves. So, the relationship between DDR or HRR genes including PALB2 and immunotherapy cannot be generalized, and each gene needs more specific studies to prove its role. In addition, whether PALB2 can produce synergistic effects with other gene variants in DDR is not explained in this study, and more studies are needed for further exploration.

In conclusion, PALB2 mutation in this study was not associated with immunotherapy. These findings suggest that PALB2 may not be a prognostic biomarker for NSCLC patients receiving immunotherapy. In our study, we only conducted statistical analysis on NSCLC patients with PALB2, so it has certain limitations and needs more studies to verify it.

The datasets presented in this article are not readily available because making data publicly available would compromise patient confidentiality, and sequencing data contain sequencing algorithm and other core trade information of 3D Medicines Inc. Requests to access the datasets should be directed to the corresponding author JZ (E-mail address: drzjxcn@126.com).

The studies involving human participants were reviewed and approved by the Research Ethics Committee of the First Affiliated Hospital of Guangzhou University. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

Conception and design: JZ, XC, and ST. Acquisition of data: ML, CZ, and MH. Analysis and interpretation of data: CZ and YZ. Writing, review, and/or revision of the manuscript: XH and YZ. Study supervision: JZ, XC, and ST. All authors contributed to the article and approved the submitted version.

This study was supported by the Clinical Application and Translational Medicine Project of First Affiliated Hospital of Guangzhou Medical University (201515-gyfyy to JZ), the Beijing Medical and Health Foundation (B19116 to JZ), and Livzon Pharmaceutical Group Inc. to JZ.

YZ, XH, and MH are employed by the company 3D Medicines Inc.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.