Since the 1980s, the human immunodeficiency virus (HIV) has spread rapidly throughout the world, infecting totally more than 70 million people and 1.7 million new infections annually (https://www.unaids.org). In the past, most HIV-infected patients died from acquired immunodeficiency syndrome (AIDS)-related diseases, including AIDS-defining malignancies (ADMs) such as Kaposi’s sarcoma, non-Hodgkin’s lymphoma, and cervical cancer in women (1). This was changed by introducing combination antiretroviral therapy (cART), which enabled HIV-infected patients to live relatively normal life (2). However, it was found that the incidence of non-AIDS-defining malignancies (NADMs) increased, including primary cancers in liver, lung, colorectal, breast, prostate, and Hodgkin’s lymphoma (3–7).

Colorectal cancer (CRC) is the most common tumor and has a worse prognosis in HIV-infected patients compared to HIV non-infected patients (7, 8). Traditionally known risk factors include obesity, excessive consumption of red meat, family history, and hereditary polyposis. Additionally, it is believed that HIV-induced immunodeficiency might increase CRC incidence (9). Nevertheless, numerous studies have revealed that CRC incidence does not differ between HIV-infected and non-infected individuals (10, 11), and there is no increase in CRC among HIV-infected individuals with low CD4 cell numbers (12). Additionally, Coghill reported that CRC incidence among HIV-infected patients in North America was only 51%-69% of the normal population (13). These different clinical findings imply that more studies are required to reveal the relationship between HIV-related immunodeficiency and CRC development (14).

CRC patients can be categorized into deficient mismatch repair proteins (dMMR) or proficient mismatch repair proteins (pMMR) groups. Compared to pMMR tumors, dMMR caused a distinct biological and clinical phenotype in CRC, including significantly increased tumor mutation burden, expression of programmed cell death 1 (PD-1), and its corresponding programmed death ligand-1 (PD-L1), and tumor-infiltrating lymphocytes (TILs) (15). High persistent disease control rates have been reported in patients with dMMR metastatic CRC treated with immune checkpoint inhibitors (ICIs) (16, 17). Despite the detection of lower TILs and insufficient ICIs efficacy in metastatic CRC patients with pMMR, several clinical trials still investigate other combination immunotherapy approaches (18). Unfortunately, CRC patients with HIV were excluded from all clinical trials examining immunotherapy, which were considered by HIV-related immunodeficiency within tumor tissues (19). Since studies have revealed no difference between the expression of TILs and PD-L1 in HIV-infected and non-HIV-infected lung cancer (20, 21), some cases of ICIs treatment for lung cancer with HIV have been reported (19). Therefore, understanding TILs and PD-1/PD-L1 expression in HIV-infected colorectal cancer is essential for developing immunotherapy for CRC patients with HIV. In the present study, PD-1/PD-L1 expression and immune cell infiltration in CRC tissues were analyzed, and correlations with clinical characteristics were examined in HIV-infected and non-HIV-infected patients with CRC.

With the development of effective cART, the lifespan of people living with HIV is greatly prolonged. The number of HIV-infected people aged 65 years or older is expected to increase once in the next decade. The proportion of NADMs that accounted for about 20% of all tumors in the pre-cART era has reached 70%. In the next ten years, one of NADMs will be more common than all ADMs combined (24). Nevertheless, cART does not completely remove HIV from the infected patient. If cART is stopped, HIV rapidly rebounds and continues to destroy the immune system. Regarding efficacy and tolerance of cancer drugs when combined with cART, the standard cancer treatment remains lower for people living with HIV (19).

The neo-antigen-targeting antitumor immune response is sometimes potent enough to eradicate the tumor by infiltrating the immune cells. Regarding colorectal cancer, tumors with high infiltrate of CD8 and T helper 1 (CD4) type cells had a better prognosis than those with a low infiltrate (15, 25). However, immune checkpoint proteins suppress the immunological attack against tumor cells, such as PD-1. Blocking the interaction between PD-1 on immune effector cells and PD-L1 on tumor cells has been demonstrated to reverse the suppression of antitumor immunity and has revealed significant antitumor effects in different malignancies, including advanced colorectal cancer (CRC) (17). It was found that CRC patients had a poorer prognosis within HIV-infected than non-infected patients (7). From the standpoint of antitumor immunity, HIV infection-induced immunosuppression is likely to be associated with poor CRC prognosis. However, conclusive evidence for this assumption has not yet been obtained. This study compared immune- and cancer-related antigens in CRC tissue specimens of patients with and without HIV infection. We did not observe a significant difference in the number of positive cells including CD4, CD8, and CD56 and the number of cells expressing PD-1 and PD-L1 between propensity score-matched cohorts. Therefore, it was hypothesized that HIV infection does not affect lymphocytic infiltration within the tumor. In contrast, the reason for the poor prognosis of colorectal cancer with HIV is uncertain, possibly due to the initial diagnosis at an advanced stage ( Table S1 ) and inadequate treatment (8).

HIV infection is associated with the progressive loss of T cells, and functional impairment of HIV-specific CD8 and CD4 T cells ultimately leads to the inability of the host immune system to maintain control of HIV, accelerating disease progression (26). One reason for T cell exhaustion is increased PD-1 expression on the surface of CD4 and CD8 T cells and inhibitory ligand PD-L1 on cells of a myeloid lineage (27). Continuous viral antigen stimulation persists even in patients receiving antiretroviral therapy, resulting in sustained activation of HIV-specific CD8 T cells (28). Tumor-specific CD8 T cells can become PD-1 positive cells by the influence of continuously activated HIV-specific CD8 T cells (21). The observations support that PD-L1/PD-1 interactions play a key role in regulating the immune environment in HIV infection and may induce an immune environment favorable for tumor development. However, these assumptions remain vague and lack evidences. In the present study, we compare the co-expression of PD-1 on CD4, CD8, and CD56 tumor-infiltrating cells, and PD-L1 on tumor cells between HIV-infected and non-HIV-infected groups. Without immunosuppression of T cells in peripheral blood, we did not identify upregulated expression of PD-1 in tumor-infiltrating lymphocytes and PD-L1 in tumor cells. Peripheral blood CD4/CD8 ratio is used as an indicator to monitor the severity of HIV infection. This value was closely associated with CD4 tumor-infiltrating cells, but was not observed to affect PD-1 and PD-L1 expression in tumors ( Figure S1 ). In a study of non-small cell lung cancer, it was demonstrated that tumors in HIV patients probably had a greater sensitivity towards immunotherapy (29). Consequently, further studies are required to elucidate the underlying mechanisms, especially in colorectal cancer.

HIV infection remains an exclusion criterion for cancer clinical trials of ICIs. Prospective data on the safety and activity of these novel anticancer agents in people living with HIV (PLHIV) are unavailable. In case reports, treatment with ICIs in PLHIV revealed similar impacts and side effects as in non-infected individuals, and no enhancement of HIV replication was observed (19). However, these studies have mainly focused on non-small cell lung cancer and solid tumor, for which data on colorectal cancer treatment are lacking. We hope that by describing the immune cell infiltration and expression of PD-1/PD-L1 in HIV colorectal cancer patients, we can provide theoretical evidence for future development of ICIs treatment.

Approximately 15% of CRC patients have poorly differentiated dMMR tumors and have histologic heterogeneity and increased tumor-infiltrating lymphocytes compared to pMMR tumors (15, 30). However, the microenvironment of pMMR tumors still presents activation on prime antigen-specific CD4 and CD8 T cells of cancer immunity (31, 32). In this study, only pMMR tumors were selected for immunofluorescence analysis, and the accumulation of CD4 and CD8 T cells within tumors was observed. We did not detect a decrease in T-cell infiltration in HIV group, which may provide a theoretical basis for subsequent development of enhanced therapy with effector T-cell (33, 34). We also plan to continue recruiting dMMR-CRC cases in a follow-up study to investigate whether there are differences in TILs between groups. Another limitation of the present study is the small number of patients selected for multiplexed immunofluorescence analysis, which may influence the outcomes. By utilizing propensity scores and pair testing, patient backgrounds were widely equalized to minimize the influence.

HIV-infected colorectal cancer (CRC) patients had similar tumor-infiltrating lymphocytes (CD4 and CD8 T cells) compared to HIV-uninfected controls and significantly similar PD-1 expression on TILs and tumor PD-L1 expression. No significant immunosuppression was detected in the tumor microenvironment with well-controlled HIV infection. Our findings support the inclusion of HIV-infected CRC patients in future clinical trials evaluating the efficacy of immunotherapy or immune checkpoint inhibitors directed against these tumor-specific T cells or molecules.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by Shanghai Public Health Clinical Center. The patients/participants provided their written informed consent to participate in this study.

LD conceived the study. LD and SL co-wrote the paper. YC and QW collected all data and undertook the search. All authors contributed to the article and approved the submitted version.

The present study was supported by the clinical research program of Shanghai Public Health Clinical Center (KY-GW-2021-20).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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