The role of the immune system in brain metastasis

Metastatic brain tumors are the most common brain tumors in adults. With numerous successful advancements in systemic treatment of most common cancer types, brain metastasis is becoming increasingly important in the overall prognosis of cancer patients. Brain metastasis of peripheral tumor is the result of complex interplay of primary tumor, immune system and central nervous system microenvironment. Once formed, brain metastases hide behind the blood brain barrier and become inaccessible to chemotherapies that are otherwise successful in targeting systemic cancer. The approval of immune checkpoint inhibitors for several common cancers such as advanced melanoma and lung cancers brings with it the opportunity and obligation to further understand the mechanisms of immunosuppression by tumors that spread to the brain as well as the interaction between the brain environment and tumor microenvironment. In this review paper we define the central role of the immune system in the development of brain metastases. We performed a comprehensive review of the literature to outline the molecular mechanisms of immunosuppression used by tumors and how the immune system interacts with the central nervous system to facilitate brain metastasis. In particular we discuss the tumor-type-specific mechanisms of metastasis of cancers that preferentially metastasize to the brain as well as the therapies that effectively modulate the immune response, such as immune checkpoint inhibitors and vaccines

A Systematic Review of Sellar and Parasellar Brown Tumors: An Analysis of Clinical, Diagnostic, and Management Profiles

Objective To systematically review and analyze clinical, diagnostic, and management trends in sellar and parasellar brown tumors reported in existing literature. Methods In this systematic review, PubMed, Ovid MEDLINE, Scopus, and Google Scholar databases were searched for reported cases of sellar/parasellar brown tumors. Relevant titles and abstracts were screened in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol. Articles meeting inclusion criteria were subjected to data extraction, summarization, and analysis. A rare case of parasellar brown tumor was also presented. Results Eight reports (including the current report) were eligible for inclusion. Mean patient age was 42.75 years. Reported symptoms included visual disturbances (n = 6), headache (n = 5), fatigue (n = 3), nausea/vomiting (n = 2), chest pain (n = 1), neck pain (n = 1), and dysphagia (n = 1). In cases where computed tomography findings were provided (n = 6), lesions were noted to be expansile and lytic. Lesions were hyperintense on T2-weighted magnetic resonance imaging (66.7%) and demonstrated contrast enhancement (83.3%). Histology unanimously showed multinucleated giant cells in a fibrovascular connective tissue stroma. Dramatic symptom resolution was noted in all patients who underwent resection of the sellar/parasellar brown tumor (n = 4; 50%). Conclusions Sellar/parasellar brown tumors are a rare, tertiary manifestation of hyperparathyroidism and can be elusive to diagnose. Diagnosis requires a high index of clinical suspicion in addition to comprehensive biochemical testing, imaging, and histopathologic analysis. Surgical extirpation is favored in cases where the lesion is causing compressive symptoms, or if it is unresponsive to management of hyperparathyroidism

Transient increase in IL-10-producing cells after natalizumab initiation and high frequency in individuals with PML.

<p>PBMC from all studied MS patients were stimulated with SEB. Background-subtracted frequency of memory CD4 T cells producing IL-10 is shown. <i>P</i> value from month 0 to month 1 is the result of Wilcoxon matched-pairs rank sum test. Panel A shows longitudinal samples from MS patients treated with natalizumab who did not have PML, and Panel B shows samples from 4 individuals with natalizumab-associated PML.</p

JCV-specific T cell responses in subjects with PML.

<p>Panel A shows the total response to JCV. For each of 4 subjects with PML, the summed frequency of memory CD4 (left) and CD8 (right) T cells producing IFNγ, TNF, IL-2 or IL-10 (indicated by colors) in response to all JCV peptides is shown. Red bars indicate frequency of cells producing IFNγ, including those that produce any combination of IL-2 and TNF in addition to IFNγ. The responses for subjects PML-1 and PML-2 are not significantly above background in these samples. Panel B shows the JCV-specific IL-10 response in subjects PML-3 and PML-4. Subjects PML-1, 2, 3 and 4 were sampled 2 weeks, 2 months, 4 months and 5 years, respectively, after diagnosis with PML.</p

T cell responses to JC virus target each viral protein.

<p>PBMC from individuals with MS treated with natalalizumab who did not have PML were stimulated with JCV peptide pools or costimulatory molecules alone (negative control) for 6 hours. Panel A shows memory CD4 T cells from 3 samples; Panel C shows memory CD8 T cells from 3 samples. The fluorescence intensity of IFNγ and TNF are shown on the X and Y-axes, respectively. Panels B and D show baseline pre-treatment responses from all eight longitudinal subjects with MS, with the background-subtracted magnitude of the response to each JCV protein depicted by colored bars. Responses were measured by production of any combination of IFNγ, TNF and IL-2, using Boolean gates and then background subtracting from each Boolean population.</p

Magnitude and functional profile of JCV and CMV-specific T cells do not change upon treatment.

<p>PBMC from individuals with MS treated with natalalizumab who did not have PML were stimulated with JCV peptide pools, CMV pp65 peptide pool or costimulatory molecules alone (negative control) for 6 hours. A response was considered positive if the frequency of memory T cells producing IFNγ, TNF or IL-2 was higher in the peptide-stimulated cells than in those stimulated with costimulatory molecules alone. Response size was calculated by measuring the frequency of cells producing each Boolean combination of cytokines, and subtracting the frequency of these cells in the negative control. Summing the background-subtracted Boolean subsets gave the total frequency of cytokine-producing memory T cells specific for the peptide pool. The total response to JCV (Panel A) was calculated by summing the frequency of cells specific for each of the 5 JCV peptide pools. The functional profile of the response is shown in the pie charts above, with the blue slice representing the proportion of responding cells that produce all 3 cytokines, the red slices representing the proportion of cells that produce a combination of 2 cytokines, and the green slices representing the proportion of cells that produce only 1 cytokine. Panel B shows the frequency of CD4 (left) and CD8 (right) memory T cells responding to the CMV pp65 peptide pool.</p

Risk of COVID-19 after natural infection or vaccinationResearch in context

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health