Introduction
Peritoneal carcinomatosis (PC) carries a poor prognosis and was considered as a terminal stage of disease until the introduction of cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy. Cytoreductive surgery (CRS) is a radical procedure that aims to completely resect all intra-abdominal tumour tissue. Hyperthermic intraperitoneal chemotherapy (HIPEC) involves local delivery of high-dose chemotherapeutics in warmed solutions with the intention of optimizing tumouricidal activity and minimizing systemic toxicity. Although CRS-HIPEC is regarded a promising treatment for patients with PC secondary to gastrointestinal [
1] or ovarian cancer [
2] without extra-abdominal disease, there remain unanswered questions about eligibility criteria and effectiveness of CRS-HIPEC beyond highly selected patient groups [
3].
Patient selection for CRS-HIPEC is important for achieving complete cytoreduction, hence a useful therapeutic effect. Apart from the absence of widespread tumour dissemination or tumour complicated with obstruction or perforation, current guidelines emphasize patients’ fitness for therapy as a key eligibility criterion. Only patients with an ECOG (Eastern Cooperative Oncology Group) performance status of ≤ 2 points should be considered to receive a CRS-HIPEC procedure, which generally selects for younger patients [
4].
Even if acceptable rates of mortality and morbidity are achievable through narrow patient selection, survival outcomes with CRS-HIPEC may only be marginally superior to other surgical approaches such as CRS alone [
5]. The need for better strategies to control intra-abdominal disease recurrence after CRS-HIPEC has sparked interest in possible combination therapies, such as anti-PD-1 or other immune checkpoint inhibitors (ICIs) [
6,
7]. A better understanding of
T cell immunity in patients with widespread intraperitoneal metastases could lead to a more rational approach to immunotherapy for PC. Hence, in this study, we investigated the immune phenotype of
T cells isolated from peripheral blood and omental fat of patients with PC secondary to colorectal carcinoma and compared these to patients with advanced colorectal carcinoma but without PC.
Discussion
Here, we compared immune phenotypes between patients with PC from CRC and patients with loco-regional CRC without distant metastasis. We made two interesting immunological observations about these two groups of patients: First, PC patients had a higher frequency of naïve CD8+ T cells compared to CG patients both in peripheral blood and omental adipose tissue. And second, PC patients had a CD4+ Tmem subset of adipose tissue-derived T cells that expressed elevated levels of PD-1, TIGIT, and VISTA.
We observed a significant over-representation of naïve CD8
+ T cells in peripheral blood and omental fat in PC patients compared to non-PC patients. Notably, PC patients selected for CRS-HIPEC were generally younger than CG patients. Age-related decline of naïve CD8
+ T cell frequency is a well-described phenomenon in healthy and diseased people [
12]. Therefore, selection of PC patients according to fitness for surgery, which biases towards younger patients, is a likely explanation for this finding. Nevertheless, a more naïve
T cell profile may be favourable in terms of response to immunotherapy [
13].
A third of our PC patients received preoperative chemotherapy and all of them were metachronous PC. These patients were treated according to guidelines for management of colorectal cancer so that they received folinic acid, 5-fluorouracil, oxaliplatin or irinotecan (FOLFOX/ FOLFOXIRI). Some patients additionally received bevacizumab, a therapeutic antibody against vascular endothelial growth factor, to inhibit neovascularization. We cannot exclude that prior chemotherapy, rather than tumour-related effects, might account for some of the immunological differences observed in our study [
14] since temporal changes have been reported in the peripheral immune cell composition and cytokine production in response to chemoradiation therapy in rectal cancer patients. Especially, the proportion of CD4
+ T cells among total lymphocytes was relatively higher than that of CD8
+ T cells during chemoradiation therapy. However, after treatment termination, the proportion of CD8
+ T cells increased and was similar to the proportion of CD4
+ T cells [
15].
We speculate that the over-representation of CD4
+ Tmem cells expressing inhibitory receptors from adipose tissue of PC patients reflects tumour-driven
T cell exhaustion [
16]. In particular, we discovered CD4
+ Tmem over-expressing PD-1, TIGIT, and VISTA. Therefore, these receptors might represent valuable therapeutic targets in PC patients. Defining an approach to address these targets is challenging. In particular, systemic drug administration has the disadvantage of having limited access to the abdominal compartment and the possibility of producing systemic toxicity [
17]. Therefore, the direct administration of immunotherapies into the peritoneal cavity represents an interesting strategy.
So far, catumaxomab had been the only in Europe approved monoclonal antibody used for intraperitoneal application and treatment of malignant ascites. Catumaxomab is a trivalent antibody that crosslinks CD3
+ T cells with epithelial cell adhesion molecule (EpCAM) expressing tumours in the presence of FcR-bearing myeloid antigen presenting cells, which primes cellular and humoral responses against tumour antigens [
18]. Beneficial effects of catumaxomab cotreatment were reported in several studies in patients with a range of tumour entities [
19]. Of interest, Ströhlein et al
. [
20] showed an acceptable safety profile for intraperitoneal use of catumaxomab in patients with PC secondary to colon, gastric, and pancreatic cancer . Recent investigations in murine models of PC provide encouraging preclinical results for intraperitoneal immunotherapy [
21]. However, catumaxomab was voluntarily withdrawn due to commercial reasons. Another immunotherapy approach is the treatment with Chimeric Antigen Receptor (CAR)-T cells. CAR-T cell therapy was first used in haematological malignancies and obtained promising results. This led to the development of CAR-T cells for targeting solid tumours. However, their use in solid tumour and their efficacy have not at all achieved the expected results [
22]. Second-generation CAR-T cells targeting CEA to treat peritoneal carcinomatosis have been used in murine model, demonstrating that local peritoneal infusion of CAR-T cells was superior to systemic administration [
23]. Furthermore, using a PC mouse model of MC38 colon cancer, it has been shown that intraperitoneal immunotherapy with oncolytic vaccinia virus is able to restore peritoneal anticancer immunity and potentiate immune checkpoint blockade to suppress PC and malignant ascites [
24].
In conclusion, our study revealed a more naïve profile for CD8+ T cells in peripheral blood and omental fat of PC patients. More importantly, we discovered an over-representation of CD4+ memory T cells expressing inhibitory receptors in omental fat of PC patients, but not in their blood or adipose tissue of non-PC patients, which suggests local anti-tumour immunity might be compromised. The favourable systemic immune profile of PC patients leads us to the proposition that intraperitoneal application of therapeutic antibodies against PD-1, TIGIT, or VISTA could enhance their local efficacy whilst minimizing systemic toxicity.
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