Inherited defects in natural killer cells shape tumor immune microenvironment, clinical outcome and immunotherapy response

Abstract

27Tumor immune microenvironment (TIME) plays an important role in metastasis and 28 immunotherapy. However, it has been not much known how to classify TIMEs and how TIMEs are 29 genetically regulated. Here we showed that tumors were classified into TIME-rich, -intermediate and -30 poor subtypes which had significant differences in clinical outcomes, abundances of tumor-infiltrating 31 lymphocytes (TILs), degree of key immune programs' activation, and immunotherapy response across 32 13 common cancer types (n= ~6,000). Furthermore, TIME-intermediate/-poor patients had significantly 33 more inherited genetic defects (i.e., functional germline variants) in natural killer (NK) cells, antigen 34 processing and presentation (APP) and Wnt signaling pathways than TIME-rich patients, and so did 35 cancer patients than non-cancer individuals (n=4,500). These results suggested that individuals who 36 had more inherited defects in NK cells, APP and Wnt pathways had higher risk of developing 37 cancers. Moreover, in the 13 common cancers the number of inheritably defected genes of NK 38 cells was significantly negative-correlated with patients' survival, TILs' abundance in TIMEs and 39 immunotherapy response, suggesting that inherited defects in NK cells alone were sufficient to shape 40 TILs' recruitment, clinical outcome and immunotherapy response, highlighting that NK cell activation 41 was required in the 13 cancer types to drive the recruitment of immune troops into TIMEs. Thus, we 42proposed that cancer was a disease of NK cell inherited deficiencies. These results had implications in 43 identifying of high-risk individuals based on germline genomes, implementing precision cancer 44 prevention by adoptive transfer of healthy NK cells, and improving existing immunotherapies by 45 combining of adoptive NK cell transfer (i.e., converting TIME-intermediate/-poor tumors into TIME-46 rich tumors) in and anti-PD-1 or CAR-T therapy. 47 48 49

The new role for an old guy: MYC as an immunoplayer

“…It was shown that MYC is a direct downstream target for sensors involved in antitumor response of NK cells in vivo, endoplasmic reticulum stress sensor inositol-requiring enzyme 1 (IRE1α) and its substrate transcription factor X-boxbinding protein 1 (Han Dong et al, 2019). These findings are in line with the previously made speculations that inheritable defect of two key antitumor activities of NK cells-cytotoxicity and immune cell recruitment-results in low-efficient cancer immunosurveillance and a high risk of tumour development and formation of metastases (Sibbitt et al, 1984;Xu et al, 2018). Thus, it is reasonable to conclude that MYC influences the Elimination phase of immunoediting, affecting innate immunity in both cancer cell-dependent manner (via CD47-dependent mechanisms) and innate cells-intrinsic manner.…”

Abnormal Expression of c-Myc Oncogene in NK Cells in Patients with Cancer

“…Since the revealed defects of NK cells in cancer patients do not depend on stage of disease, localization, and metastatic spread, these defects rather precede cancer development than are the result of tumor growth. In line with this, recent “-omic” data (tumor RNA-seq (RNA sequencing) and whole-exome sequences of germline genomes) of The Cancer Genome Atlas of cancer patients ( n = ~6,000) representing 13 common cancer types suggest that individuals who have inherited defects in NK cells experience a high risk of developing cancers [32]. Specifically, in all most common cancers, defects of the NK-specific-genes (i.e., NKD+ NK cell receptors) alone were sufficient to establish the critical correlations with patient survival and tumor infiltration by cytotoxic T cells.…”

“…The authors speculate that inheritable defected of two key antitumor activities of NK cells—cytotoxicity and immune cell recruitment—results in low-efficient cancer immunosurveillance and high risk of tumor development and formation of metastases. The authors propose that “cancer is largely a disease of NK cell deficiencies” [32].…”

Germline Mutations and Their Clinical Applications in Cancer

“…Another aspect of our study focused on classifying tumor immune microenvironments (TIMEs). Interestingly, we were able to classify TIMEs into three distinct groups commonly found in all cancer types: TIME-rich (or 'immunehot' tumors), TIME-intermediate (or 'immune-cold' tumors) and TIME-poor (or 'immune-desert tumors') [10]. By comparing germline genomics of the three TIME groups, we found that the number of inherited defected NK-cell related genes was negatively correlated with patient survival, TIL abundance in TIMEs, suggesting that inherited defects in NK cells alone were sufficient to shape TILs recruitment and therefore, clinical outcome and immunotherapy response.…”

“…We have shown that inheritably functional variants of breast cancer patients significantly predicted tumor recurrence [7,8], and the risk of developing breast, brain and other cancers [9]. Furthermore, we have shown that inheritably functional variants in natural killer cells (i.e., natural killer [NK] cells, an immune cell type) in cancer patients affected tumor-infiltrating lymphocytes (TILs) and survival [10]. These results bring a paradigm-shifting view about the roles of germline genomes in cancer.…”