Intratumoral immunoglobulin isotypes predict survival in lung adenocarcinoma subtypes

Abstract

BackgroundThe role of tumor-infiltrating B-cells (TIBs) and intratumorally-produced antibodies in cancer-immunity interactions essentially remains terra incognita. In particular, it remains unexplored how driver mutations could be associated with distinct TIBs signatures and their role in tumor microenvironment.MethodsHere we analyzed associations of immunoglobulin isotypes and clonality with survival in TCGA RNA-Seq data for lung adenocarcinoma (LUAD), stratifying patients into 12 driver mutation and phenotypic tumor subgroups.ResultsWe revealed several unexpected associations between TIBs behavior and prognosis. Abundance and high proportion of IgG1 isotype, and low proportion of IgA among all intratumorally produced immunoglobulins were specifically associated with improved overall survival for KRASmut but not KRASwt LUAD, revealing the first link between a driver mutation and B-cell response. We found specific IgG1 signature associated with long survival, which suggests that particular specificities of IgG1+ TIBs could be beneficial in KRASmut LUAD. In contrast to our previous observations for melanoma, highly clonal IgG1 production by plasma cells had no meaningful effect on prognosis, suggesting that IgG1+ TIBs may exert a beneficial effect in KRASmut cases in an alternative way, such as efficient presentation of cognate antigens or direct B cell attack on tumor cells. Notably, a high proportion of the IgG1 isotype is positively correlated with the non-silent mutation burden both in the general LUAD cohort and in most patient subgroups, supporting a role for IgG1+ TIBs in antigen presentation. Complementing the recent finding that the presence of stromal IgG4-producing cells is associated with a favorable prognosis for patients with stage I squamous cell carcinoma, we show that the abundance of IgG4-producing TIBs likewise has a strong positive effect on overall survival in STK11mut and proximal proliferative subgroups of LUAD patients. We hypothesize that the positive role of IgG4 antibodies in some of the lung cancer subtypes could be associated with reported inability of IgG4 isotype to form immune complexes, thus preventing immunosuppression via activation of the myeloid-derived suppressor cell (MDSC) phenotype.ConclusionsWe discover prominent and distinct associations between TIBs antibody isotypes and survival in lung adenocarcinoma carrying specific driver mutations. These findings indicate that particular types of tumor-immunity relations could be beneficial in particular driver mutation context, which should be taken into account in developing strategies of cancer immunotherapy and combination therapies. Specificity of protective B cell populations in specific cancer subgroups could become a clue to efficient targeted immunotherapies for appropriate cohorts of patients.

BTK Has Potential to Be a Prognostic Factor for Lung Adenocarcinoma and an Indicator for Tumor Microenvironment Remodeling: A Study Based on TCGA Data Mining

“…However, the other study showed that CD40-activated B cell was a vigorous antigen-presenting cell and was able to induce the effect of antitumor immunity (31). A recent study revealed a correlation between the amounts of tumor-infiltrating B cells and the survival of LUAD patients with specific mutation driver, which suggested that tumor-infiltrating B cells might be a symbol for the specific mutation in lung cancer cells (32). Therefore, the positive correlation between the amounts of B-cell memory and BTK expression in LUAD patients suggested that BTK might be responsible for the preservation of immune-active status in TME.…”

Identification of 5-Gene Signature Improves Lung Adenocarcinoma Prognostic Stratification Based on Differential Expression Invasion Genes of Molecular Subtypes

“…used genome-wide mRNA expression profile to establish the robust molecular subtypes of LUAD by using a combination method [ 32 ]. Many studies have also found different LUAD subtypes, which have different immune infiltration characteristics and molecular mechanisms [ 33 , 34 ]. More detailed genetic classification of tumors may be more effective for clinical precision therapy.…”

Measuring Intratumoral Heterogeneity of Immune Repertoires

“…Clonal expansions were identified only when comparing the samples obtained from X and Y fragments ( Figure 5C), and lower correlation of clonal frequencies between X and Y fragments compared to replicate samples allowed to estimate the level of immunoglobulin heterogeneity ( Figure 5D). Along with the composition, clonality, and hypermutation of intratumorally-produced antibodies, the proportion of distinct antibody isotypes may also be a crucial parameter with prominent prognostic value, as has been shown for human melanoma and subtypes of lung adenocarcinoma and bladder cancer (5,8). Like clonal frequencies, isotype proportions are heterogeneous across tumor tissue and subject to sampling noise, but also generally correlate well between replicates produced at the level of single-cell suspensions (Figure 5E).…”

“…Analysis of T and B cell repertoires has become a valuable and powerful tool for characterizing the immune response, complementing other high-content approaches such as transcriptome analysis and mass cytometry (1)(2)(3). Both T and B cell repertoires have been shown to be predictive of survival for cancer patients (4)(5)(6)(7)(8) and for assessing response to checkpoint immunotherapy (9)(10)(11)(12)(13).…”