Tryptophan 2,3‐dioxygenase in tumor cells is associated with resistance to immunotherapy in renal cell carcinoma

Abstract

Indoleamine 2,3‐dioxygenase 1 (IDO1) is a key enzyme associated with immunomodulation through its regulation of the tryptophan‐kynurenine (Kyn) pathway in advanced cancers, including metastatic renal cell carcinoma (mRCC). However, the failure of IDO1 inhibitors when used in combination with immune checkpoint inhibitors (ICIs), as observed in clinical trials, raises a number of questions. This study aimed to investigate the association of tryptophan 2,3‐dioxygenase (TDO) and IDO1 with cancer development and resistance to immunotherapy in patients with RCC. In our analysis of RCC tissue samples, tissue Kyn levels were elevated in advanced‐stage RCC and correlated well with TDO expression levels in RCC tumor cells. In patients with mRCC, TDO rather than IDO1 was expressed in RCC tumor cells, showing a strong association with Kyn expression. Furthermore, immunohistochemical staining of TDO was strongly associated with the staining intensity of forkhead box P3, as well as ICI therapy response and survival in patients with mRCC. Our study is the first to show that TDO expression in tumor tissues is associated with progression and survival, confirming its potential as a predictive biomarker of primary resistance to immunotherapy in patients with mRCC. Our findings suggest that strategies aimed at inhibiting TDO, rather than IDO1, in combination with ICI therapy may aid in the control of mRCC progression.

The Gut Microbiota Activates AhR Through the Tryptophan Metabolite Kyn to Mediate Renal Cell Carcinoma Metastasis

“…The composition of the gut microbiota determines several tryptophan metabolites because they are catabolism products of gut microbiota. These tryptophan-derived microbial catabolites are important signaling molecules in the host and the microorganisms ( 24 , 25 ). Targeted metabolomics studies have shown that RCC patients have elevated Kyn pathway metabolites ( 26 ).…”

Failure of Immunotherapy—The Molecular and Immunological Origin of Immunotherapy Resistance in Lung Cancer

“…Based on the presence or absence of the immune system in the tumor microenvironment, we can distinguish three immunophenotypes of tumors: (1) "Hot" tumors, which are strongly infiltrated by T lymphocytes and many inflammatory signals are presented; (2) "cold" tumors, which are scanted of any immune cells infiltration nor inflammatory signs; (3) tumors with immune exclusion, where immune cells are at the periphery or within the stromal tissue [10][11][12]. It is postulated that high density of T lymphocytes and pre-existing of primed immune response in "hot" tumors are associated with higher clinical benefits from immunotherapy [10][11][12][13][14][15]. The immunotherapy resistance associated with an impaired function of the immune system, also referred in the literature as tumor extrinsic mechanism, could be considered on several levels of immune system dysfunction and could be associated with specific tumor immunophenotypes [8,16,17].…”

“…However, we should remember that the blood vessels growth into the tumor tissue occurs in a quite disorganized and chaotic manner. This situation of resistance is most commonly associated with the occurrence of tumors with immune exclusion, where immune cells are at the periphery or within the stromal tissue [11,12,15].…”

Multidiscipline Immunotherapy-Based Rational Combinations for Robust and Durable Efficacy in Brain Metastases from Renal Cell Carcinoma

“…The link between very long chain fatty acid-containing lipids and response to ICI in RCC can be explained by enhanced peroxisome signaling in activated T cells, which leads to a metabolic switch to fatty acid catabolism [104]. Lastly, increased conversion of TRP to kynurenine by IDO leads to inhibition of T cell function and is involved in the regulation of the immunosuppressive TME of mRCC [54,105].…”