The NSCLC TME consists of tumor cells and stromal cells, including distinct immune cell subsets. CD36, a scavenger receptor expressed in multiple cell types mediating lipid uptake and immunological recognition, plays an important role in TME remodeling. In this study, we discovered the suppressive function of CD36
+CD8
+ T cells in NSCLC and demonstrated a higher proportion of CD36
+CD8
+ T cells in NSCLC tissues than that in non-tumor tissues, which was positively correlated with TNM stage. From the best of our knowledge, the role of CD36 in NSCLC cells proliferation and migration [
14], and its function in macrophage polarization during acute lung injury [
15] had been demonstrated. However, no research was conducted in NSCLC to explore the expression and distribution of CD36 in tumor-infiltrating T lymphocytes. And the mechanism of CD36
+CD8
+ T cells leading to tumor progression was not clear. Some recent studies mainly focused on the role of CD36 in regulating cholesterol or fatty acids metabolism and subsequent ferroptosis [
11,
16,
17]. Our research in NSCLC showed that anti-tumor function of CD36
+CD8
+ T cells was impaired, with less production of GZMB and INF-γ and higher expression of PD-1 and TIGIT. The decreased cytotoxicity and increased suppressive molecules contribute to tumor growth and evasion, which result in the poor outcomes of NSCLC patients. More importantly, a negative correlation between cytotoxic cytokines and CD36
+CD8
+ T cells infiltration was observed, as well as a positive correlation between CD36
+CD8
+ T cells infiltration and the expression of immune checkpoints. Further exploration found that suppressive immune components increased in the TME with high proportion of CD36
+CD8
+ T cells. More immunosuppressive cells (Tregs and M2) were observed in high CD36
+CD8
+ T cells group. Except for Th1 cells, main effector cells (CD4
+ T, NK, M1, DC cells) showed no differences between high and low CD36
+CD8
+ T cells infiltration groups. Additionally, the proportion of CD36
+CD8
+ T cells was positively correlated with the infiltration of Treg and M2 cells. The mechanisms of increased Treg and M2 cells infiltration in the TME had been explored [
18,
19], but no evidence confirmed their relationship with the increase of CD36
+CD8
+ T cells. Nevertheless, since Treg and M2 cells can directly inhibit the function of CD8
+ T cells, and Treg cells can selectively sustain M2-like macrophage metabolic fitness [
20], the high expression of CD36 and the high infiltration of Treg and M2 cells establish a vicious circle of immunosuppression, which together impair the function of CD8
+ T cells, promoting tumor immune escape and poor prognosis of NSCLC patients. CD8
+ T cells have long been thought to exert anti-tumor effects in different solid tumors including lung cancer. However, a study from Mori et al. reported that CD8
+ T cells didn’t indicate the anti-tumor immunity in NSCLC [
21] and high infiltration of CD8
+ T cells didn’t predict better prognosis. Our study also found that the proportion of CD8
+ T cells was not associated with patient prognosis in NSCLC, but higher percentage of CD36
+CD8
+ T cells, as an independent factor, could predict both worse OS and RFS. This implied that in addition to distribution and number of CD8
+ T cells, the state of CD8
+ T cells was also important to induce anti-tumor immunity [
22,
23].
We further analyzed the prognosis of patients who accepted postoperative chemotherapy at different stages and found that higher infiltration of CD36
+CD8
+ T cells was indicative of worse prognosis. This suggests that CD36 may lead to inferior response to chemotherapy in NSCLC patients by impairing anti-tumor immune functions. Targeting CD36 combined with chemotherapy is expected to bring better clinical benefits for NSCLC patients. Immune-checkpoint inhibitors (ICIs), particularly inhibitors of PD-1/PD-L1, have been confirmed great benefits in treatment of NSCLC [
24‐
27], but there is still a considerable proportion of patients with little efficacy. Clinically, postoperative chemotherapy based on platinum is the first line therapy for most operable NSCLC patients. And combining ICIs with chemotherapy has been shown to improve survival in NSCLC patients [
28,
29]. Nonetheless, many patients still respond poorly to this combination treatment. Therefore, the search for new immunotherapeutic targets is urgent. We attempted to block CD36 and detect changes in CD8
+ T cell function, after employment of SSO, the cytotoxic function of CD36
+CD8
+ T cells was partially restored without altering the immune checkpoints, which indicated the potential of CD36 as a therapeutic target for NSCLC. Wang et al. [
30] recently showed that immunotherapy-activated CD8
+ T cells enhanced ferroptosis-specific lipid peroxidation in tumor cells, improving the anti-tumor efficacy of immunotherapy. CD36 was proved to mediate ferroptosis [
10], and it seemed to contradict our aim of blocking CD36 to improve the anti-tumor immune response. However, through dual-color immunofluorescence, we found that CD36 was highly expressed on T cells rather than tumor cells in NSCLC (Fig.
2C and D), and CD36 blockage will exert little effect on the ferroptosis in tumor cells theoretically. Therefore, combination of other therapies including chemotherapy and CD36 blockage could promisingly enhance anti-tumor effects in NSCLC.
There were several limitations of our study. Firstly, we revealed the correlation of CD36
+CD8
+ T cells with TME and the prognosis of NSCLC; however, we didn’t explore the effect of CD36 alone, including how CD36 was regulated and whether there was a cause-and-effect connection between CD36 and TME or prognosis of NSCLC. And thus, a comprehensive understanding of CD36 in regulating TME and NSCLC progression is needed. Secondly, CD36 possibly had a greater prognostic impact on more extensive tumors (stage II-III) regardless of chemotherapy receipt. This indicated that it was not the best way to compare the prognosis (OS and RFS) among these patients who underwent surgery and adjuvant chemotherapy in either CD36
+CD8
+ T cells high or low group to explore the impact of CD36 on the response to chemotherapy. Instead, to really establish that CD36
+CD8
+ T cells impacted the immune response to chemotherapy specifically, the inferior response should be shown in patients with stage II-III NSCLC who had surgery and chemotherapy, and not shown in patients who had surgery alone. However, adjuvant postoperative chemotherapy is the standard of care in all patients at stage II-III [
31], which means comparison can only be made in patients who underwent both surgery and chemotherapy. Thirdly, more explorations into mechanisms of CD36
+CD8
+ T cells inducing immunosuppressive TME in vitro and in vivo are needed. In addition, the effect and safety of combined CD36 blockage and chemotherapy need to be verified in animal models.