CCL7 recruits cDC1 to promote antitumor immunity and facilitate checkpoint immunotherapy to non-small cell lung cancer

Abstract

The efficacy of checkpoint immunotherapy to non-small cell lung cancer (NSCLC) largely depends on the tumor microenvironment (TME). Here, we demonstrate that CCL7 facilitates anti-PD-1 therapy for the KrasLSL−G12D/+Tp53fl/fl (KP) and the KrasLSL−G12D/+Lkb1fl/fl (KL) NSCLC mouse models by recruiting conventional DC 1 (cDC1) into the TME to promote T cell expansion. CCL7 exhibits high expression in NSCLC tumor tissues and is positively correlated with the infiltration of cDC1 in the TME and the overall survival of NSCLC patients. CCL7 deficiency impairs the infiltration of cDC1 in the TME and the subsequent expansion of CD8+ and CD4+ T cells in bronchial draining lymph nodes and TME, thereby promoting tumor development in the KP mouse model. Administration of CCL7 into lungs alone or in combination with anti-PD-1 significantly inhibits tumor development and prolongs the survival of KP and KL mice. These findings suggest that CCL7 potentially serves as a biomarker and adjuvant for checkpoint immunotherapy of NSCLC.

Blocking ActRIIB signaling and restoring appetite reverses cachexia and improves survival in mice with lung cancer

“…More importantly, we find that the combination of Ana with ActRIIB-Fc significantly improved body composition, activity, and overall survival. The degree of survival improvement we observed is on par with the effects of chemotherapy and immunotherapy in this model 61,62 .…”

IL‐36γ and IL‐36Ra Reciprocally Regulate NSCLC Progression by Modulating GSH Homeostasis and Oxidative Stress‐Induced Cell Death

“…Interleukin family cytokines play essential roles in inflammation that has been implicated in the initiation and development of lung cancer. [ 41 ] In an attempt to screen cytokines and chemokines that were differentially expressed in NSCLC tumor tissues versus normal lung tissues, [ 42 , 43 ] we identified that IL1F9 (encoding IL‐36 γ , an IL‐36 cytokine member) but not IL1F6 or IL1F8 (encoding IL‐36 α or IL‐36 β , respectively) was highly expressed in the tumor tissues compared to the normal tissues (Cohort 1) (Figure S1A and Table S1 , Supporting Information). This observation was confirmed with another independent cohort of tumors and normal lung tissues from NSCLC patients (Cohort 2) (Figure S1B and Table S2 , Supporting Information), and was consistent with the data from the TCGA database (Figure S1C and Table S3 , Supporting Information).…”

“…Three cohorts of human NSCLC samples were collected and analyzed in this study. [ 43 ] Cohort 1 was collected from June to August of 2013 containing 10 paired NSCLC tumor and normal tissues that were used to screen differentially expressed cytokines. Cohort 2 was collected from November of 2013 to March of 2014 containing 43 paired NSCLC tumor and normal tissues that were used for confirmation of the screened cytokines from Cohort 1.…”

“…Kras LSL‐G12D/+ (#0 08179), Tp53 fl/fl (#0 08462), Lkb1 fl/fl (#01 4143) mice were purchased from the Jackson Laboratory as previously described. [ 43 ] C57BL/6 mice were purchased from GemPharmatech Co., Ltd (Nanjing, China). Il1f9 +/− (#032395‐UCD) and Il1f5 +/− (#032393‐UCD) mice were obtained from the Mutant Mouse Resource and Research Center (MMRRC) and were crossed with C57BL/6 mice for six generations before subsequent studies.…”

Characteristics of hypoxic tumor microenvironment in non-small cell lung cancer, involving molecular patterns and prognostic signature

“…TFRC promotes the proliferation and metastasis of cancer cells by up-regulating the expression of AXIN2 to accelerate the progress of epithelial ovarian cancer (41). Transforming growth factor (TGFA) stimulates cell growth and proliferation, and its overexpression is associated with the survival rate of patients with many tumors (42 NFKB1 [ 7] XRCC6 [ 7] PGK1 [ 6] ENO1 [ 5] PFKP [ 5] TEK [ 5] SPP1 [ 4] TFRC [ 4] ADM [ 2] GAPDH [ 2] STC1 [ 2] DDIT3 [ 1] FGF3 [ 1] PLAUR [ 1] TGFA [ 1] EPAS1 [10] NFKB1 [ 7] XRCC6 [ 7] PGK1 [ 6] ENO1 [ 5] PFKP [ 5] TEK [ 5] SPP1 [ 4] TFRC [ 4] ADM [ 2] GAPDH [ 2] STC1 [ 2] DDIT3 [ 1] FGF3 [ 1] PLAUR [ 1] TGFA [ 1] * P < 0.001 NFKB1 [10] TEK [ 8] PFKP [ 5] STC1 [ 5] EPAS1 [ 4] PLAUR [ 4] TFRC [ 4] SPP1 [ 3] GAPDH [ 2] PGK1 [ 2]…”