STK11/LKB1 Deficiency Promotes Neutrophil Recruitment and Proinflammatory Cytokine Production to Suppress T-cell Activity in the Lung Tumor Microenvironment

Abstract

STK11/LKB1 is among the most commonly inactivated tumor suppressors in non-small cell lung cancer (NSCLC), especially in tumors harboring KRAS mutations. Many oncogenes promote immune escape, undermining the effectiveness of immunotherapies, but it is unclear whether inactivation of tumor suppressor genes such as STK11/LKB1 exert similar effects. In this study, we investigated the consequences of STK11/LKB1 loss on the immune microenvironment in a mouse model of KRAS-driven NSCLC. Genetic ablation of STK11/LKB1 resulted in accumulation of neutrophils with T cell suppressive effects, along with a corresponding increase in the expression of T cell exhaustion markers and tumor-promoting cytokines. The number of tumor-infiltrating lymphocytes was also reduced in LKB1-deficient mouse and human tumors. Furthermore, STK11/LKB1 inactivating mutations were associated with reduced expression of PD-1 ligand PD-L1 in mouse and patient tumors as well as in tumor-derived cell lines. Consistent with these results, PD-1 targeting antibodies were ineffective against Lkb1-deficient tumors. In contrast, treating Lkb1-deficient mice with an IL-6 neutralizing antibody or a neutrophil-depleting antibody yielded therapeutic benefits associated with reduced neutrophil accumulation and proinflammatory cytokine expression. Our findings illustrate how tumor suppressor mutations can modulate the immune milieu of the tumor microenvironment, and they offer specific implications for addressing STK11/LKB1 mutated tumors with PD-1 targeting antibody therapies.

Synergy of radiotherapy and PD-1 blockade in Kras-mutant lung cancer

“…An analysis exerted by Schabath et al on 442 tumors of lung adenocarcinoma patients confirmed the differential biological association of STK11 and TP53 in KRAS-mutant tumors (11). In line with these findings, our own preclinical analysis revealed that loss of the tumor suppressor Stk11/Lkb1 in Kras-mutated tumors induced marked changes within the tumor immune microenvironment in comparison to Kras-mutated tumors specified by accumulation of tumor-associated neutrophils, increased expression of T cell exhaustion markers, and secretion of tumor-promoting cytokines (12). Furthermore, these tumors were not responsive to αPD-1 blockade.…”

“…Despite careful intrathoracic application of Adeno-Cre and close clinical monitoring, we were unable to follow treatment response in these mice for longer periods due to rapid tumor growth. Mice treated with either RT or αPD-1 alone recapitulated our previously reported therapeutic responses and demonstrated significant inhibition or slowed tumor enlargement compared with naive tumors, respectively (8,12). The antitumor efficacy of RT was significantly better than PD-1 blockade in Kras/Lkb1 tumors.…”

“…Furthermore, we reported that the drug sensitivity of Kras-driven mNSCLC is dramatically impacted depending on the additional loss of either Lkb1 or Trp53 (7). More recently, we observed that Lkb1 inactivation in mNSCLC causes significant changes within the tumor microenvironment by mediating accumulation of TAN and reduction of tumor-infiltrating lymphocytes, increased expression of T cell inhibitory markers, and secretion of tumor-promoting cytokines (12). Additionally, we found that Lkb1 alteration is negatively correlated with PD-L1 expression on murine and human tumor cells.…”

cAMP/CREB-regulated LINC00473 marks LKB1-inactivated lung cancer and mediates tumor growth

“…On the other hand, LKB1 loss impaired the responses of KRAS mutant NSCLC to docetaxel monotherapy; the combination therapy of docetaxel and the MEK inhibitor selumetinib; or dual inhibition of the PI3K and MEK pathways (16,17). Additionally, LKB1 mutations were associated with the modulation of immune microenvironments, thus potentially impacting immunotherapeutic outcomes (18,19). The current data emphasize the need to determine tumor LKB1 status for patient stratification for evaluating therapeutic responses and identifying effective treatments.…”

Stromal Lkb1 deficiency leads to gastrointestinal tumorigenesis involving the IL-11–JAK/STAT3 pathway

“…Recently, several reports have identified increased inflammatory signaling upon Lkb1 loss in different cell and tissue contexts, such as in skeletal muscle (12), macrophages (13), T cells (14), and lung cancer (15), implicating Lkb1 as a suppressor of inflammatory pathways. In PJS patients and in Lkb1 +/-mice, inhibition of cyclooxygenase-2 with the selective inhibitor celecoxib demonstrated partial efficiency in reducing PJS polyposis by reducing the size but not the number of tumors (16).…”