Cluster of differentiation 8 and programmed cell death ligand 1 expression in triple-negative breast cancer combined with autosomal dominant polycystic kidney disease and tuberous sclerosis complex: a case report

The presence of TSC2 and PKD1 gene deletions should be considered in the clinical assessment of TSC in children with early-onset PKD and in all patients with ADPKD who develop end-stage renal failure prior to the fourth or fifth decade of life [5]. Dysfunction of the C-terminal tail of PKD1 in TSC2/PKD1 CGS was suggested to play a crucial role in renal prognosis [6].

Kleczko et al. suggested that T cells, specifically CD8⁺ T cells, had a functional role in ADPKD progression [7]. Therefore, the use of immune-oncology agents that target this pathway may represent a novel therapeutic approach for ADPKD [7]. First, patients with TSC2/PKD1 CGS have high mutation burden and produce several neoantigens, which are produced by cancer cells that have not been previously recognized by the immune system. Second, the neoantigens have very high immunologic potential, because they evade thymic selection and central tolerance. Finally, multiple gene deletions, as well as monogenic deficiency, induce the production of cytotoxic immune cells, such as CD8⁺ T cells, and infiltration of CD8⁺ T cells around the tumor leads to neoantigen production. Endometrial cancer with polymerase epsilon ultra-mutation and microsatellite instability hypermutation has been shown to have an active tumor microenvironment (TME) with increased numbers of neoantigens and tumor-infiltrating lymphocytes (TILs) [8]. Interestingly, this patient exhibited an increased number of peripheral blood cells, such as myeloid-derived suppressor cells (MDSCs), which inhibit immunologic function. In our previous report, patients with stage II breast cancer had high blood levels of MDSC cells [9]. We speculated that CD8⁺ T cells may compete with MDSCs in the TME.

Increase in the number of both CD8⁺ T cells and TILs is associated with survival. Moreover, the high PD-L1 expression in patients with relatively high CD8⁺ T cell count indicates an adaptive immune mechanism. In the present case, the diffuse positive immunohistochemistry staining for CD8 and PD-L1 in breast cancer tissue was consistent with neoantigen production due to high mutation burden. In addition, in a murine model of pulmonary lymphangioleiomyomatosis, increased PD-L1 expression was observed in Tsc2-null lesions [10].

In a previous report on TNBC [11], T cells were shown to decrease in density as they moved in from the boundary of tumor cell clusters; this density increased as the T cells approached the center. Although tumor mutational burden was evaluated in that study, it was not prognostic and did not correlate with PD-L1 or CD8 gene expression. In patients with TNBC, PD-L1 is expressed mainly on tumor-infiltrating immune cells, rather than on the tumor cells, and can inhibit the anticancer immune response. Therefore, inhibition of programmed cell death 1 (PD-1) and PD-L1 may be a useful treatment strategy. Unresectable locally advanced or metastatic TNBC is an aggressive disease with poor outcomes. Nanoparticle albumin-bound (nab)-paclitaxel may enhance the anticancer activity of atezolizumab. Based on the results of available trials [12, 13], this combination of chemotherapy and immunotherapy clearly benefited patients with PD-L1-positive tumors and may be considered for recurrent cases. On the other hand, first-line pembrolizumab monotherapy was shown to have a manageable safety profile and durable antitumor activity therapy for patients with PD-L1-positive metastatic TNBC [14]. Merck announced the phase 3 KEYNOTE-119 trial on Keytruda® (pembrolizumab) as monotherapy for the second-line or third-line treatment of patients with metastatic TNBC [15]. However, that trial did not meet its pre-specified primary endpoint of superior overall survival (OS), compared with that of chemotherapy with capecitabine, eribulin, gemcitabine, or vinorelbine. As per the study protocol, the other endpoints were not formally tested because the primary endpoint of OS was not met.

At present, research to identify biomarkers of good response to immunotherapy is still ongoing. Some of the possible biomarkers that are being explored include TILs, tumor PD-L1 expression, and tumor mutational burden. However, all the mechanisms involved in immunotherapy have not been completely understood, thereby making it difficult to identify a biomarker that can broadly work for all the approved immunotherapies. For patients with PD-L1-positive tumors (that is, ≥ 1% PD-L1 expression on tumor-infiltrating immune cells), first-line treatment with nab-paclitaxel and atezolizumab was recommended, when available [16]. Further characterization of the immune microenvironment may highlight the targets for immune-based therapy of TNBC.

To develop an immunohistochemical scoring algorithm that includes PD-L1 expression for both tumor and immune cells (that is, combined positive score) [17], the varying clinicopathologic features and survival outcomes of TNBC need to be determined according to the different histologic subtypes. Medullary carcinoma and apocrine adenocarcinoma have excellent prognosis, whereas mixed lobular–ductal carcinoma and metaplastic carcinoma are the most aggressive subtypes [18]. TNBC can be categorized into six different molecular subtypes that are characterized by distinct biological features. The different molecular clusters described were basal-like 1, basal-like 2, immunomodulatory, mesenchymal, mesenchymal stem-like, and luminal androgen receptor. These TNBC molecular subtypes can be targeted by specific therapies [19] and have substantial genomic heterogeneity with distinct patterns of genomic alterations and putative underlying driver mutations [20].

In fact, identification of biomarkers that can guide treatment decisions in TNBC remains a clinically unmet need. Understanding the mechanisms that drive resistance is the key to the development of novel therapeutic strategies that can help prevent metastatic disease and, ultimately, improve survival in this patient population [21].

At a glance, breast cancer appears to be unrelated to PKD. The endonuclease III-like 1 (NTHL1) gene may be involved in DNA repair and is present in the 68-bp region, downstream of the TSC2 gene. The TSC2 gene is located upstream of the NTHL1 gene by 5′-to-5′ (head-to-head) placement, and the promoters of both NTHL1 and TSC2 genes overlap. The NTHL1 gene was said to be causative of multiple cancers, including breast cancer [22]. Furthermore, the gene is located in a 3′-to-3′ (tail-to-tail) orientation with the solute carrier family 9 isoform A3 regulatory factor 2 (SLC9A3R2) gene [23]. The SLC9A3R2 gene of the Na+/H+ exchange carrier controlling element is present in the 8778-bp region upstream of the TSC2 gene. These genes were thought to be located on chromosome 16p13.3, from the centromere side, in the order of TSC2, NTHL1, and SLC9A3R2 [24]. The SLC9A3R2 gene is broadly expressed in fat tissue and is a housekeeping gene that consistently showed low variance as the normalizing genes in the microarray profiles of all breast cancer datasets [25].

One of our patient’s younger brothers had ADPKD and died at a young age, whereas the other younger brother had intellectual impairment, which was most likely RTS [26]. RTS comprises multiple congenital anomalies and is characterized by intellectual disability, postnatal growth deficiency, microcephaly, broad thumbs and halluces, and dysmorphic facial features. It is caused by heterozygous mutation in the gene that encodes the transcriptional coactivator cyclic adenosine monophosphate (cAMP)-response element-binding protein (CREB) binding protein (CREBBP) on chromosome 16p13.3 [27]. Inhibition of hypothalamic CREBBP results in profound obesity, impaired glucose homeostasis, and increased food intake [28]. Surprisingly, one of our patient’s younger brothers has DM, is stout, and may have CREBBP gene deficiency. The unique feed–forward signaling loop of cAMP−CREB−glycogen synthase kinase 3 beta (GSK3β)−cAMP is potentially self-sustaining, and blocking it at any point would break this vicious cycle and significantly reduce PKD progression [29]. Therefore, the younger brother was unlikely to have PKD.